CA3145507A1 - Clinical methods and pharmaceutical compositions employing ampa receptor antagonists to treat glioblastoma and other cancers - Google Patents
Clinical methods and pharmaceutical compositions employing ampa receptor antagonists to treat glioblastoma and other cancers Download PDFInfo
- Publication number
- CA3145507A1 CA3145507A1 CA3145507A CA3145507A CA3145507A1 CA 3145507 A1 CA3145507 A1 CA 3145507A1 CA 3145507 A CA3145507 A CA 3145507A CA 3145507 A CA3145507 A CA 3145507A CA 3145507 A1 CA3145507 A1 CA 3145507A1
- Authority
- CA
- Canada
- Prior art keywords
- cancer
- ampar
- pmp
- substituted
- perampanel
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 166
- 238000000034 method Methods 0.000 title claims abstract description 102
- 208000005017 glioblastoma Diseases 0.000 title claims description 48
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 11
- 229940098747 AMPA receptor antagonist Drugs 0.000 title description 8
- 239000000775 AMPA receptor antagonist Substances 0.000 title description 8
- 229960005198 perampanel Drugs 0.000 claims abstract description 165
- 239000005557 antagonist Substances 0.000 claims abstract description 117
- 201000011510 cancer Diseases 0.000 claims abstract description 105
- 150000001875 compounds Chemical class 0.000 claims abstract description 99
- 102000003678 AMPA Receptors Human genes 0.000 claims abstract description 49
- 108090000078 AMPA Receptors Proteins 0.000 claims abstract description 49
- -1 Perampanel compound Chemical class 0.000 claims abstract description 45
- PRMWGUBFXWROHD-UHFFFAOYSA-N perampanel Chemical compound O=C1C(C=2C(=CC=CC=2)C#N)=CC(C=2N=CC=CC=2)=CN1C1=CC=CC=C1 PRMWGUBFXWROHD-UHFFFAOYSA-N 0.000 claims description 165
- 230000001093 anti-cancer Effects 0.000 claims description 130
- 238000011282 treatment Methods 0.000 claims description 92
- 239000003814 drug Substances 0.000 claims description 63
- 229940079593 drug Drugs 0.000 claims description 53
- 239000003112 inhibitor Substances 0.000 claims description 42
- 230000005855 radiation Effects 0.000 claims description 30
- 239000002246 antineoplastic agent Substances 0.000 claims description 27
- 238000002560 therapeutic procedure Methods 0.000 claims description 23
- 239000003795 chemical substances by application Substances 0.000 claims description 22
- 238000011319 anticancer therapy Methods 0.000 claims description 17
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 16
- 238000002512 chemotherapy Methods 0.000 claims description 16
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 14
- 201000002528 pancreatic cancer Diseases 0.000 claims description 14
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 14
- 230000007423 decrease Effects 0.000 claims description 12
- 229960004002 levetiracetam Drugs 0.000 claims description 11
- 229940002612 prodrug Drugs 0.000 claims description 11
- 239000000651 prodrug Substances 0.000 claims description 11
- 230000004083 survival effect Effects 0.000 claims description 10
- 229930003827 cannabinoid Natural products 0.000 claims description 9
- 239000003557 cannabinoid Substances 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 108090000623 proteins and genes Proteins 0.000 claims description 9
- 229940123445 Tricyclic antidepressant Drugs 0.000 claims description 8
- 229940124597 therapeutic agent Drugs 0.000 claims description 8
- FTALBRSUTCGOEG-UHFFFAOYSA-N Riluzole Chemical compound C1=C(OC(F)(F)F)C=C2SC(N)=NC2=C1 FTALBRSUTCGOEG-UHFFFAOYSA-N 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
- 239000002207 metabolite Substances 0.000 claims description 7
- 229960004181 riluzole Drugs 0.000 claims description 7
- 238000001356 surgical procedure Methods 0.000 claims description 7
- YBZSGIWIPOUSHY-UHFFFAOYSA-N troriluzole Chemical compound NCC(=O)NCC(N(CC(NC=1SC2=C(N=1)C=CC(=C2)OC(F)(F)F)=O)C)=O YBZSGIWIPOUSHY-UHFFFAOYSA-N 0.000 claims description 7
- 229940121629 troriluzole Drugs 0.000 claims description 7
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 6
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 claims description 6
- 102000004169 proteins and genes Human genes 0.000 claims description 6
- 108091035539 telomere Proteins 0.000 claims description 6
- 210000003411 telomere Anatomy 0.000 claims description 6
- 102000055501 telomere Human genes 0.000 claims description 6
- 238000013518 transcription Methods 0.000 claims description 6
- 230000035897 transcription Effects 0.000 claims description 6
- 239000004066 vascular targeting agent Substances 0.000 claims description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 102000004190 Enzymes Human genes 0.000 claims description 5
- 108090000790 Enzymes Proteins 0.000 claims description 5
- 101000916644 Homo sapiens Macrophage colony-stimulating factor 1 receptor Proteins 0.000 claims description 5
- 102100028198 Macrophage colony-stimulating factor 1 receptor Human genes 0.000 claims description 5
- 206010027476 Metastases Diseases 0.000 claims description 5
- 230000003281 allosteric effect Effects 0.000 claims description 5
- 239000003430 antimalarial agent Substances 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 102000008394 Immunoglobulin Fragments Human genes 0.000 claims description 4
- 108010021625 Immunoglobulin Fragments Proteins 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
- 229940125715 antihistaminic agent Drugs 0.000 claims description 4
- 239000000739 antihistaminic agent Substances 0.000 claims description 4
- 229960000074 biopharmaceutical Drugs 0.000 claims description 4
- 239000003102 growth factor Substances 0.000 claims description 4
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 239000006186 oral dosage form Substances 0.000 claims description 4
- 229940123208 Biguanide Drugs 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 108020004414 DNA Proteins 0.000 claims description 3
- 230000006820 DNA synthesis Effects 0.000 claims description 3
- 108010009202 Growth Factor Receptors Proteins 0.000 claims description 3
- 102000009465 Growth Factor Receptors Human genes 0.000 claims description 3
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 3
- 102000004243 Tubulin Human genes 0.000 claims description 3
- 108090000704 Tubulin Proteins 0.000 claims description 3
- 239000004037 angiogenesis inhibitor Substances 0.000 claims description 3
- 230000000078 anti-malarial effect Effects 0.000 claims description 3
- 150000004283 biguanides Chemical class 0.000 claims description 3
- 230000022131 cell cycle Effects 0.000 claims description 3
- 229960003668 docetaxel Drugs 0.000 claims description 3
- 238000001990 intravenous administration Methods 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 claims description 3
- 229940075993 receptor modulator Drugs 0.000 claims description 3
- 230000019491 signal transduction Effects 0.000 claims description 3
- IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 claims description 2
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 claims description 2
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 claims description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 2
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 239000012623 DNA damaging agent Substances 0.000 claims description 2
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 claims description 2
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 claims description 2
- 102000003951 Erythropoietin Human genes 0.000 claims description 2
- 108090000394 Erythropoietin Proteins 0.000 claims description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 claims description 2
- 208000022072 Gallbladder Neoplasms Diseases 0.000 claims description 2
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 claims description 2
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 claims description 2
- 102000002812 Heat-Shock Proteins Human genes 0.000 claims description 2
- 108010004889 Heat-Shock Proteins Proteins 0.000 claims description 2
- 208000017604 Hodgkin disease Diseases 0.000 claims description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 2
- 102000014150 Interferons Human genes 0.000 claims description 2
- 108010050904 Interferons Proteins 0.000 claims description 2
- 239000002067 L01XE06 - Dasatinib Substances 0.000 claims description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 229930012538 Paclitaxel Natural products 0.000 claims description 2
- NAVMQTYZDKMPEU-UHFFFAOYSA-N Targretin Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C(=C)C1=CC=C(C(O)=O)C=C1 NAVMQTYZDKMPEU-UHFFFAOYSA-N 0.000 claims description 2
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 2
- 206010057644 Testis cancer Diseases 0.000 claims description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 2
- 230000001399 anti-metabolic effect Effects 0.000 claims description 2
- 230000002927 anti-mitotic effect Effects 0.000 claims description 2
- 229940033495 antimalarials Drugs 0.000 claims description 2
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 claims description 2
- 229960001467 bortezomib Drugs 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 229960000928 clofarabine Drugs 0.000 claims description 2
- WDDPHFBMKLOVOX-AYQXTPAHSA-N clofarabine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F WDDPHFBMKLOVOX-AYQXTPAHSA-N 0.000 claims description 2
- 229960002448 dasatinib Drugs 0.000 claims description 2
- 229960003603 decitabine Drugs 0.000 claims description 2
- 229940108890 emend Drugs 0.000 claims description 2
- GTTBEUCJPZQMDZ-UHFFFAOYSA-N erlotinib hydrochloride Chemical compound [H+].[Cl-].C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 GTTBEUCJPZQMDZ-UHFFFAOYSA-N 0.000 claims description 2
- 229960005073 erlotinib hydrochloride Drugs 0.000 claims description 2
- 229940105423 erythropoietin Drugs 0.000 claims description 2
- 201000004101 esophageal cancer Diseases 0.000 claims description 2
- 229960002258 fulvestrant Drugs 0.000 claims description 2
- 201000010175 gallbladder cancer Diseases 0.000 claims description 2
- 239000005556 hormone Substances 0.000 claims description 2
- 229940088597 hormone Drugs 0.000 claims description 2
- 229960002751 imiquimod Drugs 0.000 claims description 2
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 claims description 2
- 239000002955 immunomodulating agent Substances 0.000 claims description 2
- 229940121354 immunomodulator Drugs 0.000 claims description 2
- 230000002584 immunomodulator Effects 0.000 claims description 2
- 229940079322 interferon Drugs 0.000 claims description 2
- 210000003734 kidney Anatomy 0.000 claims description 2
- 229960004942 lenalidomide Drugs 0.000 claims description 2
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 claims description 2
- 229960003881 letrozole Drugs 0.000 claims description 2
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000029559 malignant endocrine neoplasm Diseases 0.000 claims description 2
- 208000026037 malignant tumor of neck Diseases 0.000 claims description 2
- 229960000801 nelarabine Drugs 0.000 claims description 2
- IXOXBSCIXZEQEQ-UHTZMRCNSA-N nelarabine Chemical compound C1=NC=2C(OC)=NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O IXOXBSCIXZEQEQ-UHTZMRCNSA-N 0.000 claims description 2
- 238000011275 oncology therapy Methods 0.000 claims description 2
- 229960001756 oxaliplatin Drugs 0.000 claims description 2
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 claims description 2
- 229960001592 paclitaxel Drugs 0.000 claims description 2
- 229960004641 rituximab Drugs 0.000 claims description 2
- IVDHYUQIDRJSTI-UHFFFAOYSA-N sorafenib tosylate Chemical compound [H+].CC1=CC=C(S([O-])(=O)=O)C=C1.C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 IVDHYUQIDRJSTI-UHFFFAOYSA-N 0.000 claims description 2
- 229960000487 sorafenib tosylate Drugs 0.000 claims description 2
- 229940099419 targretin Drugs 0.000 claims description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 2
- 201000003120 testicular cancer Diseases 0.000 claims description 2
- 229960003433 thalidomide Drugs 0.000 claims description 2
- 201000002510 thyroid cancer Diseases 0.000 claims description 2
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims description 2
- 229960002190 topotecan hydrochloride Drugs 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 206010046766 uterine cancer Diseases 0.000 claims description 2
- 230000003612 virological effect Effects 0.000 claims description 2
- 101100463133 Caenorhabditis elegans pdl-1 gene Proteins 0.000 claims 2
- 229930186949 TCA Natural products 0.000 claims 2
- 230000001154 acute effect Effects 0.000 claims 2
- 229940088598 enzyme Drugs 0.000 claims 2
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 claims 2
- QXLQZLBNPTZMRK-UHFFFAOYSA-N 2-[(dimethylamino)methyl]-1-(2,4-dimethylphenyl)prop-2-en-1-one Chemical compound CN(C)CC(=C)C(=O)C1=CC=C(C)C=C1C QXLQZLBNPTZMRK-UHFFFAOYSA-N 0.000 claims 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 claims 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 claims 1
- 229940122964 Deacetylase inhibitor Drugs 0.000 claims 1
- 108010074604 Epoetin Alfa Proteins 0.000 claims 1
- 102000003972 Fibroblast growth factor 7 Human genes 0.000 claims 1
- 108090000385 Fibroblast growth factor 7 Proteins 0.000 claims 1
- 102000015696 Interleukins Human genes 0.000 claims 1
- 108010063738 Interleukins Proteins 0.000 claims 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 claims 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims 1
- 208000000453 Skin Neoplasms Diseases 0.000 claims 1
- 206010062129 Tongue neoplasm Diseases 0.000 claims 1
- 229940124599 anti-inflammatory drug Drugs 0.000 claims 1
- 239000008365 aqueous carrier Substances 0.000 claims 1
- 229960002756 azacitidine Drugs 0.000 claims 1
- 229960003388 epoetin alfa Drugs 0.000 claims 1
- 229960000255 exemestane Drugs 0.000 claims 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims 1
- 229960005144 gemcitabine hydrochloride Drugs 0.000 claims 1
- 229940121372 histone deacetylase inhibitor Drugs 0.000 claims 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 claims 1
- 210000004072 lung Anatomy 0.000 claims 1
- 229960002404 palifermin Drugs 0.000 claims 1
- 210000000496 pancreas Anatomy 0.000 claims 1
- 238000007911 parenteral administration Methods 0.000 claims 1
- 229960001744 pegaspargase Drugs 0.000 claims 1
- 108010001564 pegaspargase Proteins 0.000 claims 1
- 150000004492 retinoid derivatives Chemical class 0.000 claims 1
- 201000000849 skin cancer Diseases 0.000 claims 1
- 229960001796 sunitinib Drugs 0.000 claims 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 claims 1
- 201000006134 tongue cancer Diseases 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 44
- 210000003169 central nervous system Anatomy 0.000 abstract description 17
- 230000003389 potentiating effect Effects 0.000 abstract description 12
- 230000000174 oncolytic effect Effects 0.000 abstract description 6
- 210000004027 cell Anatomy 0.000 description 53
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 45
- 230000008901 benefit Effects 0.000 description 34
- 229960004964 temozolomide Drugs 0.000 description 29
- 230000000694 effects Effects 0.000 description 28
- 230000001976 improved effect Effects 0.000 description 21
- 150000003839 salts Chemical group 0.000 description 20
- 230000001225 therapeutic effect Effects 0.000 description 20
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 19
- 229930195712 glutamate Natural products 0.000 description 19
- 206010018338 Glioma Diseases 0.000 description 18
- 125000000217 alkyl group Chemical group 0.000 description 18
- 206010061818 Disease progression Diseases 0.000 description 17
- 230000005750 disease progression Effects 0.000 description 17
- 229940061353 temodar Drugs 0.000 description 16
- 208000032612 Glial tumor Diseases 0.000 description 15
- 230000001419 dependent effect Effects 0.000 description 14
- AUZONCFQVSMFAP-UHFFFAOYSA-N disulfiram Chemical compound CCN(CC)C(=S)SSC(=S)N(CC)CC AUZONCFQVSMFAP-UHFFFAOYSA-N 0.000 description 14
- 238000009472 formulation Methods 0.000 description 14
- 230000005764 inhibitory process Effects 0.000 description 14
- 238000012423 maintenance Methods 0.000 description 14
- 231100000419 toxicity Toxicity 0.000 description 14
- 230000001988 toxicity Effects 0.000 description 14
- 241000699670 Mus sp. Species 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- 230000003833 cell viability Effects 0.000 description 12
- HPHUVLMMVZITSG-LURJTMIESA-N levetiracetam Chemical compound CC[C@@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-LURJTMIESA-N 0.000 description 11
- 230000001404 mediated effect Effects 0.000 description 11
- 230000002411 adverse Effects 0.000 description 10
- 230000008499 blood brain barrier function Effects 0.000 description 10
- 210000001218 blood-brain barrier Anatomy 0.000 description 10
- 231100000673 dose–response relationship Toxicity 0.000 description 10
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 description 10
- 229960004640 memantine Drugs 0.000 description 10
- JGWRKYUXBBNENE-UHFFFAOYSA-N pexidartinib Chemical compound C1=NC(C(F)(F)F)=CC=C1CNC(N=C1)=CC=C1CC1=CNC2=NC=C(Cl)C=C12 JGWRKYUXBBNENE-UHFFFAOYSA-N 0.000 description 10
- 230000035755 proliferation Effects 0.000 description 10
- 239000012453 solvate Substances 0.000 description 10
- 210000004881 tumor cell Anatomy 0.000 description 10
- 102100037171 Protein JTB Human genes 0.000 description 9
- 201000007455 central nervous system cancer Diseases 0.000 description 9
- 238000011278 co-treatment Methods 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- 230000011664 signaling Effects 0.000 description 9
- 208000024891 symptom Diseases 0.000 description 9
- 230000006907 apoptotic process Effects 0.000 description 8
- 230000012010 growth Effects 0.000 description 8
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 description 8
- 238000012544 monitoring process Methods 0.000 description 8
- 238000001959 radiotherapy Methods 0.000 description 8
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 8
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 8
- 229940124530 sulfonamide Drugs 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 7
- 208000002193 Pain Diseases 0.000 description 7
- 238000007792 addition Methods 0.000 description 7
- 125000003118 aryl group Chemical group 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 125000000753 cycloalkyl group Chemical group 0.000 description 7
- 229960002563 disulfiram Drugs 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 230000001965 increasing effect Effects 0.000 description 7
- 229960003299 ketamine Drugs 0.000 description 7
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 7
- 229960003105 metformin Drugs 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 230000004614 tumor growth Effects 0.000 description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 6
- 241000282412 Homo Species 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 229940041181 antineoplastic drug Drugs 0.000 description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
- 230000000295 complement effect Effects 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 210000000130 stem cell Anatomy 0.000 description 6
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 6
- XEEQGYMUWCZPDN-DOMZBBRYSA-N (-)-(11S,2'R)-erythro-mefloquine Chemical compound C([C@@H]1[C@@H](O)C=2C3=CC=CC(=C3N=C(C=2)C(F)(F)F)C(F)(F)F)CCCN1 XEEQGYMUWCZPDN-DOMZBBRYSA-N 0.000 description 5
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 description 5
- 239000000654 additive Substances 0.000 description 5
- 229940024606 amino acid Drugs 0.000 description 5
- 239000000935 antidepressant agent Substances 0.000 description 5
- 229940005513 antidepressants Drugs 0.000 description 5
- 125000003710 aryl alkyl group Chemical group 0.000 description 5
- 230000009286 beneficial effect Effects 0.000 description 5
- 210000004556 brain Anatomy 0.000 description 5
- 229960004316 cisplatin Drugs 0.000 description 5
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 229960002464 fluoxetine Drugs 0.000 description 5
- 230000014509 gene expression Effects 0.000 description 5
- 238000003384 imaging method Methods 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 229960001962 mefloquine Drugs 0.000 description 5
- 230000002246 oncogenic effect Effects 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 230000000069 prophylactic effect Effects 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- ORQFDHFZSMXRLM-IYBDPMFKSA-N terameprocol Chemical compound C1=C(OC)C(OC)=CC=C1C[C@H](C)[C@H](C)CC1=CC=C(OC)C(OC)=C1 ORQFDHFZSMXRLM-IYBDPMFKSA-N 0.000 description 5
- 229950004034 terameprocol Drugs 0.000 description 5
- PMGQWSIVQFOFOQ-BDUVBVHRSA-N (e)-but-2-enedioic acid;(2r)-2-[2-[1-(4-chlorophenyl)-1-phenylethoxy]ethyl]-1-methylpyrrolidine Chemical compound OC(=O)\C=C\C(O)=O.CN1CCC[C@@H]1CCOC(C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 PMGQWSIVQFOFOQ-BDUVBVHRSA-N 0.000 description 4
- XEBRAMSBPJUGET-UHFFFAOYSA-N 5-[2-[(4-methylsulfonylpiperazin-1-yl)methyl]-4-morpholin-4-ylpyrazolo[1,5-a]pyrazin-6-yl]pyrimidin-2-amine Chemical compound C1CN(S(=O)(=O)C)CCN1CC1=NN2C=C(C=3C=NC(N)=NC=3)N=C(N3CCOCC3)C2=C1 XEBRAMSBPJUGET-UHFFFAOYSA-N 0.000 description 4
- 230000005778 DNA damage Effects 0.000 description 4
- 231100000277 DNA damage Toxicity 0.000 description 4
- 101000601441 Homo sapiens Serine/threonine-protein kinase Nek2 Proteins 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 102100025825 Methylated-DNA-protein-cysteine methyltransferase Human genes 0.000 description 4
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 4
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 4
- 102100037703 Serine/threonine-protein kinase Nek2 Human genes 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- QHMBSVQNZZTUGM-UHFFFAOYSA-N Trans-Cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-UHFFFAOYSA-N 0.000 description 4
- 230000008485 antagonism Effects 0.000 description 4
- 230000001430 anti-depressive effect Effects 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
- 239000012830 cancer therapeutic Substances 0.000 description 4
- QHMBSVQNZZTUGM-ZWKOTPCHSA-N cannabidiol Chemical compound OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-ZWKOTPCHSA-N 0.000 description 4
- 229950011318 cannabidiol Drugs 0.000 description 4
- ZTGXAWYVTLUPDT-UHFFFAOYSA-N cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CC=C(C)C1 ZTGXAWYVTLUPDT-UHFFFAOYSA-N 0.000 description 4
- 229940065144 cannabinoids Drugs 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 229920002301 cellulose acetate Polymers 0.000 description 4
- 229960002881 clemastine Drugs 0.000 description 4
- YNNUSGIPVFPVBX-NHCUHLMSSA-N clemastine Chemical compound CN1CCC[C@@H]1CCO[C@@](C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 YNNUSGIPVFPVBX-NHCUHLMSSA-N 0.000 description 4
- 229960002689 clemastine fumarate Drugs 0.000 description 4
- 229920001577 copolymer Polymers 0.000 description 4
- 238000013461 design Methods 0.000 description 4
- PCXRACLQFPRCBB-ZWKOTPCHSA-N dihydrocannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)C)CCC(C)=C1 PCXRACLQFPRCBB-ZWKOTPCHSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 150000002430 hydrocarbons Chemical class 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 230000036210 malignancy Effects 0.000 description 4
- 108040008770 methylated-DNA-[protein]-cysteine S-methyltransferase activity proteins Proteins 0.000 description 4
- 238000013508 migration Methods 0.000 description 4
- 229960003301 nivolumab Drugs 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 230000035515 penetration Effects 0.000 description 4
- 230000036470 plasma concentration Effects 0.000 description 4
- 102200082402 rs751610198 Human genes 0.000 description 4
- 229960002073 sertraline Drugs 0.000 description 4
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 4
- 210000003625 skull Anatomy 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 3
- MGRVRXRGTBOSHW-UHFFFAOYSA-N (aminomethyl)phosphonic acid Chemical compound NCP(O)(O)=O MGRVRXRGTBOSHW-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 3
- 208000005443 Circulating Neoplastic Cells Diseases 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 102000018899 Glutamate Receptors Human genes 0.000 description 3
- 108010027915 Glutamate Receptors Proteins 0.000 description 3
- 229940122459 Glutamate antagonist Drugs 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 3
- 102100038970 Histone-lysine N-methyltransferase EZH2 Human genes 0.000 description 3
- 101000882127 Homo sapiens Histone-lysine N-methyltransferase EZH2 Proteins 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 238000000692 Student's t-test Methods 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 230000004075 alteration Effects 0.000 description 3
- 239000003194 amino acid receptor blocking agent Substances 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 238000000540 analysis of variance Methods 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 125000004104 aryloxy group Chemical group 0.000 description 3
- 230000009789 autophagic cell death Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 230000005907 cancer growth Effects 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 230000030833 cell death Effects 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229960003677 chloroquine Drugs 0.000 description 3
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 3
- 238000004891 communication Methods 0.000 description 3
- 230000002596 correlated effect Effects 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 238000009510 drug design Methods 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000007972 injectable composition Substances 0.000 description 3
- 238000007917 intracranial administration Methods 0.000 description 3
- 201000001441 melanoma Diseases 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 230000005012 migration Effects 0.000 description 3
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 3
- ZKXZLIFRWWKZRY-KRWDZBQOSA-N n-[(2s)-3-(3,4-dihydro-1h-isoquinolin-2-yl)-2-hydroxypropyl]-6-(oxetan-3-ylamino)pyrimidine-4-carboxamide Chemical compound C([C@H](O)CN1CC2=CC=CC=C2CC1)NC(=O)C(N=CN=1)=CC=1NC1COC1 ZKXZLIFRWWKZRY-KRWDZBQOSA-N 0.000 description 3
- 210000002569 neuron Anatomy 0.000 description 3
- 230000036963 noncompetitive effect Effects 0.000 description 3
- 229960002621 pembrolizumab Drugs 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 229940083542 sodium Drugs 0.000 description 3
- 230000009044 synergistic interaction Effects 0.000 description 3
- 150000003573 thiols Chemical class 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 230000035899 viability Effects 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- CFBVGSWSOJBYGC-UHFFFAOYSA-N 2-amino-2-(2-chlorophenyl)-6-hydroxycyclohexan-1-one Chemical compound C=1C=CC=C(Cl)C=1C1(N)CCCC(O)C1=O CFBVGSWSOJBYGC-UHFFFAOYSA-N 0.000 description 2
- CMLFRMDBDNHMRA-UHFFFAOYSA-N 2h-1,2-benzoxazine Chemical group C1=CC=C2C=CNOC2=C1 CMLFRMDBDNHMRA-UHFFFAOYSA-N 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 2
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 2
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 2
- 108091092195 Intron Proteins 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 2
- 239000012270 PD-1 inhibitor Substances 0.000 description 2
- 239000012668 PD-1-inhibitor Substances 0.000 description 2
- 229940125897 PRMT5 inhibitor Drugs 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 241000286209 Phasianidae Species 0.000 description 2
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 102100034607 Protein arginine N-methyltransferase 5 Human genes 0.000 description 2
- 101710084427 Protein arginine N-methyltransferase 5 Proteins 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 2
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 2
- JACAAXNEHGBPOQ-LLVKDONJSA-N Talampanel Chemical compound C([C@H](N(N=1)C(C)=O)C)C2=CC=3OCOC=3C=C2C=1C1=CC=C(N)C=C1 JACAAXNEHGBPOQ-LLVKDONJSA-N 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102100040247 Tumor necrosis factor Human genes 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 238000002679 ablation Methods 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 238000011394 anticancer treatment Methods 0.000 description 2
- 229960003965 antiepileptics Drugs 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 238000001574 biopsy Methods 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 230000009702 cancer cell proliferation Effects 0.000 description 2
- 230000009400 cancer invasion Effects 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 125000001589 carboacyl group Chemical group 0.000 description 2
- 150000003857 carboxamides Chemical class 0.000 description 2
- 229960005243 carmustine Drugs 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940044683 chemotherapy drug Drugs 0.000 description 2
- 230000002860 competitive effect Effects 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 239000012084 conversion product Substances 0.000 description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 description 2
- 230000002380 cytological effect Effects 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000003828 downregulation Effects 0.000 description 2
- 229960004242 dronabinol Drugs 0.000 description 2
- 229940000406 drug candidate Drugs 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000000763 evoking effect Effects 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000001794 hormone therapy Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229960001330 hydroxycarbamide Drugs 0.000 description 2
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 2
- 229960004171 hydroxychloroquine Drugs 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 229940062717 keppra Drugs 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 229940121655 pd-1 inhibitor Drugs 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 description 2
- 229960003243 phenformin Drugs 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 230000002028 premature Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- 238000011127 radiochemotherapy Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 208000016691 refractory malignant neoplasm Diseases 0.000 description 2
- 210000004761 scalp Anatomy 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 238000012353 t test Methods 0.000 description 2
- 229950004608 talampanel Drugs 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 125000005309 thioalkoxy group Chemical group 0.000 description 2
- 125000005296 thioaryloxy group Chemical group 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- KTGRHKOEFSJQNS-BDQAORGHSA-N (1s)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3h-2-benzofuran-5-carbonitrile;oxalic acid Chemical compound OC(=O)C(O)=O.C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 KTGRHKOEFSJQNS-BDQAORGHSA-N 0.000 description 1
- JETBVOLWZWPMKR-WCCKRBBISA-N (2s)-2-amino-3-methylbutanoic acid;hydrochloride Chemical compound Cl.CC(C)[C@H](N)C(O)=O JETBVOLWZWPMKR-WCCKRBBISA-N 0.000 description 1
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 description 1
- WTLMVSUOVKAIHJ-UHFFFAOYSA-N 1,2,3-benzoxadiazole-5-carboxamide Chemical compound NC(=O)C1=CC=C2ON=NC2=C1 WTLMVSUOVKAIHJ-UHFFFAOYSA-N 0.000 description 1
- ZCXLTWVZYXBHJS-UHFFFAOYSA-N 1,2-benzoxazepine Chemical class O1N=CC=CC2=CC=CC=C12 ZCXLTWVZYXBHJS-UHFFFAOYSA-N 0.000 description 1
- XDHJBIYJRNFDKS-IBGZPJMESA-N 1-[(4-methoxyphenyl)methyl]-5-[(2s)-2-(pyridin-3-yloxymethyl)pyrrolidin-1-yl]sulfonylindole-2,3-dione Chemical compound C1=CC(OC)=CC=C1CN1C2=CC=C(S(=O)(=O)N3[C@@H](CCC3)COC=3C=NC=CC=3)C=C2C(=O)C1=O XDHJBIYJRNFDKS-IBGZPJMESA-N 0.000 description 1
- BKWJAKQVGHWELA-UHFFFAOYSA-N 1-[6-(2-hydroxypropan-2-yl)-2-pyridinyl]-6-[4-(4-methyl-1-piperazinyl)anilino]-2-prop-2-enyl-3-pyrazolo[3,4-d]pyrimidinone Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC=C2C(=O)N(CC=C)N(C=3N=C(C=CC=3)C(C)(C)O)C2=N1 BKWJAKQVGHWELA-UHFFFAOYSA-N 0.000 description 1
- AWBOSXFRPFZLOP-UHFFFAOYSA-N 2,1,3-benzoxadiazole Chemical class C1=CC=CC2=NON=C21 AWBOSXFRPFZLOP-UHFFFAOYSA-N 0.000 description 1
- UQNAFPHGVPVTAL-UHFFFAOYSA-N 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline Chemical compound N1C(=O)C(=O)NC2=C1C=C([N+]([O-])=O)C1=C2C=CC=C1S(=O)(=O)N UQNAFPHGVPVTAL-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical class NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- ONJRTQUWKRDCTA-UHFFFAOYSA-N 2h-thiochromene Chemical class C1=CC=C2C=CCSC2=C1 ONJRTQUWKRDCTA-UHFFFAOYSA-N 0.000 description 1
- YWJWHUVYAWSKGL-UHFFFAOYSA-N 4,6,7,8-tetrahydrochromen-5-one Chemical class C1C=COC2=C1C(=O)CCC2 YWJWHUVYAWSKGL-UHFFFAOYSA-N 0.000 description 1
- FUSNOPLQVRUIIM-UHFFFAOYSA-N 4-amino-2-(4,4-dimethyl-2-oxoimidazolidin-1-yl)-n-[3-(trifluoromethyl)phenyl]pyrimidine-5-carboxamide Chemical compound O=C1NC(C)(C)CN1C(N=C1N)=NC=C1C(=O)NC1=CC=CC(C(F)(F)F)=C1 FUSNOPLQVRUIIM-UHFFFAOYSA-N 0.000 description 1
- FEFCQDINBPEMNU-UHFFFAOYSA-N 4h-1,2-benzoxazin-3-ylidenemethanone Chemical compound C1=CC=C2ONC(=C=O)CC2=C1 FEFCQDINBPEMNU-UHFFFAOYSA-N 0.000 description 1
- GJOHLWZHWQUKAU-UHFFFAOYSA-N 5-azaniumylpentan-2-yl-(6-methoxyquinolin-8-yl)azanium;dihydrogen phosphate Chemical compound OP(O)(O)=O.OP(O)(O)=O.N1=CC=CC2=CC(OC)=CC(NC(C)CCCN)=C21 GJOHLWZHWQUKAU-UHFFFAOYSA-N 0.000 description 1
- NSMOZFXKTHCPTQ-UHFFFAOYSA-N 6-fluoro-n-[(5-fluoro-2-methoxypyridin-3-yl)methyl]-5-[(5-methyl-1h-pyrrolo[2,3-b]pyridin-3-yl)methyl]pyridin-2-amine Chemical compound COC1=NC=C(F)C=C1CNC(N=C1F)=CC=C1CC1=CNC2=NC=C(C)C=C12 NSMOZFXKTHCPTQ-UHFFFAOYSA-N 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 206010052747 Adenocarcinoma pancreas Diseases 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- UIERETOOQGIECD-UHFFFAOYSA-N Angelic acid Natural products CC=C(C)C(O)=O UIERETOOQGIECD-UHFFFAOYSA-N 0.000 description 1
- 102000010565 Apoptosis Regulatory Proteins Human genes 0.000 description 1
- 108010063104 Apoptosis Regulatory Proteins Proteins 0.000 description 1
- 241001436672 Bhatia Species 0.000 description 1
- 229940124638 COX inhibitor Drugs 0.000 description 1
- QAGYKUNXZHXKMR-UHFFFAOYSA-N CPD000469186 Natural products CC1=C(O)C=CC=C1C(=O)NC(C(O)CN1C(CC2CCCCC2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-UHFFFAOYSA-N 0.000 description 1
- 108091011896 CSF1 Proteins 0.000 description 1
- 102000007590 Calpain Human genes 0.000 description 1
- 108010032088 Calpain Proteins 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 1
- 229920008347 Cellulose acetate propionate Polymers 0.000 description 1
- DQEFEBPAPFSJLV-UHFFFAOYSA-N Cellulose propionate Chemical compound CCC(=O)OCC1OC(OC(=O)CC)C(OC(=O)CC)C(OC(=O)CC)C1OC1C(OC(=O)CC)C(OC(=O)CC)C(OC(=O)CC)C(COC(=O)CC)O1 DQEFEBPAPFSJLV-UHFFFAOYSA-N 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- 208000030808 Clear cell renal carcinoma Diseases 0.000 description 1
- 239000004859 Copal Substances 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical class OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 108700019745 Disks Large Homolog 4 Proteins 0.000 description 1
- 102000047174 Disks Large Homolog 4 Human genes 0.000 description 1
- 208000001654 Drug Resistant Epilepsy Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 239000004097 EU approved flavor enhancer Substances 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 208000000779 Gingival Neoplasms Diseases 0.000 description 1
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 1
- 102100030668 Glutamate receptor 4 Human genes 0.000 description 1
- 101710087627 Glutamate receptor 4 Proteins 0.000 description 1
- 229940086575 Glutamate release inhibitor Drugs 0.000 description 1
- 241000782205 Guibourtia conjugata Species 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 101001128694 Homo sapiens Neuroendocrine convertase 1 Proteins 0.000 description 1
- 101000588302 Homo sapiens Nuclear factor erythroid 2-related factor 2 Proteins 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- 101000601456 Homo sapiens Serine/threonine-protein kinase Nek3 Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- 102100030694 Interleukin-11 Human genes 0.000 description 1
- 102100020873 Interleukin-2 Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 206010022840 Intraventricular haemorrhage Diseases 0.000 description 1
- 241000820057 Ithone Species 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 102100028123 Macrophage colony-stimulating factor 1 Human genes 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- 239000005913 Maltodextrin Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000002030 Merkel cell carcinoma Diseases 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 108060004795 Methyltransferase Proteins 0.000 description 1
- 102000016397 Methyltransferase Human genes 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 229940099433 NMDA receptor antagonist Drugs 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- JAUOIFJMECXRGI-UHFFFAOYSA-N Neoclaritin Chemical compound C=1C(Cl)=CC=C2C=1CCC1=CC=CN=C1C2=C1CCNCC1 JAUOIFJMECXRGI-UHFFFAOYSA-N 0.000 description 1
- 206010029266 Neuroendocrine carcinoma of the skin Diseases 0.000 description 1
- 102100021878 Neuronal pentraxin-2 Human genes 0.000 description 1
- 101710155147 Neuronal pentraxin-2 Proteins 0.000 description 1
- 101100190845 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pmp-1 gene Proteins 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 102100031701 Nuclear factor erythroid 2-related factor 2 Human genes 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000282320 Panthera leo Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 108010051742 Platelet-Derived Growth Factor beta Receptor Proteins 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 108091081062 Repeated sequence (DNA) Proteins 0.000 description 1
- 108010017324 STAT3 Transcription Factor Proteins 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 102100037706 Serine/threonine-protein kinase Nek3 Human genes 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 102100024040 Signal transducer and activator of transcription 3 Human genes 0.000 description 1
- 241000320380 Silybum Species 0.000 description 1
- 235000010841 Silybum marianum Nutrition 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- ZCDNRPPFBQDQHR-SSYATKPKSA-N Syrosingopine Chemical compound C1=C(OC)C(OC(=O)OCC)=C(OC)C=C1C(=O)O[C@H]1[C@H](OC)[C@@H](C(=O)OC)[C@H]2C[C@@H]3C(NC=4C5=CC=C(OC)C=4)=C5CCN3C[C@H]2C1 ZCDNRPPFBQDQHR-SSYATKPKSA-N 0.000 description 1
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 description 1
- 229920002494 Zein Polymers 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- IYKJEILNJZQJPU-UHFFFAOYSA-N acetic acid;butanedioic acid Chemical compound CC(O)=O.OC(=O)CCC(O)=O IYKJEILNJZQJPU-UHFFFAOYSA-N 0.000 description 1
- AEMQUICCWRPKDB-UHFFFAOYSA-N acetic acid;cyclohexane-1,2-dicarboxylic acid Chemical compound CC(O)=O.OC(=O)C1CCCCC1C(O)=O AEMQUICCWRPKDB-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 229950009557 adavosertib Drugs 0.000 description 1
- 238000011360 adjunctive therapy Methods 0.000 description 1
- 238000011226 adjuvant chemotherapy Methods 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000016571 aggressive behavior Effects 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940124650 anti-cancer therapies Drugs 0.000 description 1
- 230000001348 anti-glioma Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000000573 anti-seizure effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000006851 antioxidant defense Effects 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 230000004900 autophagic degradation Effects 0.000 description 1
- XTKDAFGWCDAMPY-UHFFFAOYSA-N azaperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCN(C=2N=CC=CC=2)CC1 XTKDAFGWCDAMPY-UHFFFAOYSA-N 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000005103 brain tumor initiating cell Anatomy 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 1
- 229960001736 buprenorphine Drugs 0.000 description 1
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 230000005773 cancer-related death Effects 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 125000005026 carboxyaryl group Chemical group 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000006369 cell cycle progression Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000029412 cell redox homeostasis Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 229920006217 cellulose acetate butyrate Polymers 0.000 description 1
- 229920006218 cellulose propionate Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229940098124 cesium chloride Drugs 0.000 description 1
- 159000000006 cesium salts Chemical class 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 206010073251 clear cell renal cell carcinoma Diseases 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 230000002281 colonystimulating effect Effects 0.000 description 1
- 210000003022 colostrum Anatomy 0.000 description 1
- 235000021277 colostrum Nutrition 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000011254 conventional chemotherapy Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000003179 convulsant agent Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000036757 core body temperature Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 210000005257 cortical tissue Anatomy 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 description 1
- 208000017763 cutaneous neuroendocrine carcinoma Diseases 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- OPASRWWZEIMSOZ-UHFFFAOYSA-N cyclopentanesulfonamide Chemical class NS(=O)(=O)C1CCCC1 OPASRWWZEIMSOZ-UHFFFAOYSA-N 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000008260 defense mechanism Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000002716 delivery method Methods 0.000 description 1
- 238000000586 desensitisation Methods 0.000 description 1
- 229960001271 desloratadine Drugs 0.000 description 1
- 230000001687 destabilization Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 229940120124 dichloroacetate Drugs 0.000 description 1
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- YKZPPPNXRZHVGX-PXYKVGKMSA-L dipotassium;(2s)-2-aminobutanedioate;hydron;hydrate Chemical compound [H+].[H+].O.[K+].[K+].[O-]C(=O)[C@@H](N)CC([O-])=O.[O-]C(=O)[C@@H](N)CC([O-])=O YKZPPPNXRZHVGX-PXYKVGKMSA-L 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000009511 drug repositioning Methods 0.000 description 1
- 230000005684 electric field Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 229960004341 escitalopram Drugs 0.000 description 1
- WSEQXVZVJXJVFP-FQEVSTJZSA-N escitalopram Chemical compound C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-FQEVSTJZSA-N 0.000 description 1
- 229960005086 escitalopram oxalate Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229960005167 everolimus Drugs 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 235000019264 food flavour enhancer Nutrition 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- UPBDXRPQPOWRKR-UHFFFAOYSA-N furan-2,5-dione;methoxyethene Chemical compound COC=C.O=C1OC(=O)C=C1 UPBDXRPQPOWRKR-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-L glutamate group Chemical group N[C@@H](CCC(=O)[O-])C(=O)[O-] WHUUTDBJXJRKMK-VKHMYHEASA-L 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000009629 growth pathway Effects 0.000 description 1
- 201000005459 gum cancer Diseases 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 210000004295 hippocampal neuron Anatomy 0.000 description 1
- 230000001744 histochemical effect Effects 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 239000012493 hydrazine sulfate Substances 0.000 description 1
- 229910000377 hydrazine sulfate Inorganic materials 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 230000003463 hyperproliferative effect Effects 0.000 description 1
- 229960004801 imipramine Drugs 0.000 description 1
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
- XZZXIYZZBJDEEP-UHFFFAOYSA-N imipramine hydrochloride Chemical compound [Cl-].C1CC2=CC=CC=C2N(CCC[NH+](C)C)C2=CC=CC=C21 XZZXIYZZBJDEEP-UHFFFAOYSA-N 0.000 description 1
- 229960002102 imipramine hydrochloride Drugs 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001320 lapatinib ditosylate Drugs 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- GCICAPWZNUIIDV-UHFFFAOYSA-N lithium magnesium Chemical compound [Li].[Mg] GCICAPWZNUIIDV-UHFFFAOYSA-N 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229960002337 magnesium chloride Drugs 0.000 description 1
- 235000011147 magnesium chloride Nutrition 0.000 description 1
- 229940037627 magnesium lauryl sulfate Drugs 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 201000009020 malignant peripheral nerve sheath tumor Diseases 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- XJRBAMWJDBPFIM-UHFFFAOYSA-N methyl vinyl ether Chemical compound COC=C XJRBAMWJDBPFIM-UHFFFAOYSA-N 0.000 description 1
- 239000012022 methylating agents Substances 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 229940029985 mineral supplement Drugs 0.000 description 1
- 235000020786 mineral supplement Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 201000005962 mycosis fungoides Diseases 0.000 description 1
- AZBFJBJXUQUQLF-UHFFFAOYSA-N n-(1,5-dimethylpyrrolidin-3-yl)pyrrolidine-1-carboxamide Chemical compound C1N(C)C(C)CC1NC(=O)N1CCCC1 AZBFJBJXUQUQLF-UHFFFAOYSA-N 0.000 description 1
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 1
- 239000000025 natural resin Substances 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- QAGYKUNXZHXKMR-HKWSIXNMSA-N nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 description 1
- 229960000884 nelfinavir Drugs 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 230000007472 neurodevelopment Effects 0.000 description 1
- 201000011519 neuroendocrine tumor Diseases 0.000 description 1
- 208000029974 neurofibrosarcoma Diseases 0.000 description 1
- LHKVDVFVJMYULK-UHFFFAOYSA-N nitrosylazide Chemical compound [N-]=[N+]=NN=O LHKVDVFVJMYULK-UHFFFAOYSA-N 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 201000011330 nonpapillary renal cell carcinoma Diseases 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 102000027450 oncoproteins Human genes 0.000 description 1
- 108091008819 oncoproteins Proteins 0.000 description 1
- 230000000247 oncostatic effect Effects 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 229960001840 oprelvekin Drugs 0.000 description 1
- 108010046821 oprelvekin Proteins 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 201000002094 pancreatic adenocarcinoma Diseases 0.000 description 1
- 229960001972 panitumumab Drugs 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 210000003200 peritoneal cavity Anatomy 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 210000003281 pleural cavity Anatomy 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920002744 polyvinyl acetate phthalate Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229940068988 potassium aspartate Drugs 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229960002816 potassium chloride Drugs 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940069337 potassium orotate Drugs 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- DHBUISJCVRMTAZ-UHFFFAOYSA-M potassium;2,4-dioxo-1h-pyrimidine-6-carboxylate Chemical compound [K+].[O-]C(=O)C1=CC(=O)NC(=O)N1 DHBUISJCVRMTAZ-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229960005179 primaquine Drugs 0.000 description 1
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 239000006041 probiotic Substances 0.000 description 1
- 235000018291 probiotics Nutrition 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000005522 programmed cell death Effects 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- SJMCLWCCNYAWRQ-UHFFFAOYSA-N propane-2-sulfonamide Chemical compound CC(C)S(N)(=O)=O SJMCLWCCNYAWRQ-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 125000002577 pseudohalo group Chemical group 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 235000008160 pyridoxine Nutrition 0.000 description 1
- 239000011677 pyridoxine Substances 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 150000003246 quinazolines Chemical class 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 230000028617 response to DNA damage stimulus Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 102220279244 rs1555053901 Human genes 0.000 description 1
- 239000003772 serotonin uptake inhibitor Substances 0.000 description 1
- 239000004017 serum-free culture medium Substances 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- POECFFCNUXZPJT-UHFFFAOYSA-M sodium;carbonic acid;hydrogen carbonate Chemical compound [Na+].OC(O)=O.OC([O-])=O POECFFCNUXZPJT-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 125000004963 sulfonylalkyl group Chemical group 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 229960002812 sunitinib malate Drugs 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000007761 synergistic anti-cancer Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229950006534 syrosingopine Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229960003454 tamoxifen citrate Drugs 0.000 description 1
- FQZYTYWMLGAPFJ-OQKDUQJOSA-N tamoxifen citrate Chemical compound [H+].[H+].[H+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 FQZYTYWMLGAPFJ-OQKDUQJOSA-N 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 239000003277 telomerase inhibitor Substances 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 150000008334 thiadiazines Chemical class 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 125000005000 thioaryl group Chemical group 0.000 description 1
- UIERETOOQGIECD-ONEGZZNKSA-N tiglic acid Chemical compound C\C=C(/C)C(O)=O UIERETOOQGIECD-ONEGZZNKSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 238000011277 treatment modality Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 208000022679 triple-negative breast carcinoma Diseases 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 239000000439 tumor marker Substances 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940011671 vitamin b6 Drugs 0.000 description 1
- 235000019195 vitamin supplement Nutrition 0.000 description 1
- 230000001755 vocal effect Effects 0.000 description 1
- 229960000237 vorinostat Drugs 0.000 description 1
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/075—Ethers or acetals
- A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
- A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Disclosed herein are compositions and methods employing AMPA Receptor (AMPR) antagonist compounds to treat AMPAR positive cancers in mammalian subjects. In certain detailed embodiments the AMPAR antagonist is a Perampanel compound, effective to mediate potent oncolytic effects to prevent or reduce the severity or recurrence of a variety of cancer forms, including central nervous system (CNS) cancers.
Description
CLINICAL METHODS AND PHARMACEUTICAL COMPOSITIONS
EMPLOYING AMPA RECEPTOR ANTAGONISTS
TO TREAT GLIOBLASTOMA AND OTHER CANCERS
5 Technical Field The invention relates to drugs and clinical methods tor treating cancer in mammalian subjects. More specifically the invention relates to treating dioblastoma and other cancers that are positive for expression of AMPA-receptors.
10 Cross-Reference To Related Applications This application is related to and claims the priority benefit of prior US
Provisional Patent Application No. 62/703.952. filed July 27. 2018. and prior US
Provisional Patent Application No. 62/796.032. tiled January 23. 2019. each incorporated herein by reference in its entirety for all purposes.
Background of the Invention Cancer remains a principal mortality risk in human populations, with available drugs and treatment methods falling well short of goals to effectively treat and manage all forms of cancer in diverse patients. Today cancer persists as the second leading cause of death in the United States and in other developed nations. The US
National Cancer Institute (NCI) reported 8.2 million cancer-related deaths worldwide and 14.1 million new cases diagnosed in 2012. New cancer diagnoses are projected to rise globally to roughly 24 million by 2030.
According to current NCI statistics. an estimated 1.735.350 new eases of cancer will have been diagnosed and 609.640 cancer deaths tolled in the US for the year 2018.
The economic burdens of diagnosing and treating cancer on healthcare systems around the world arc enormous. Ns ith estimated national expenses for cancer care in the United States in 2017 approaching $150 billion. Cancer health costs will continue to rise as mean population age and cancer prevalence increase, and more expensive treatments are adopted as standards of care.
Conventional treatments for cancer typically involve a combination of surgery.
chemotherapy, radiation and hormonal therapy. Each of these treatment modalities imposes significant morbidity and added risks, tbr example adverse metabolic and reproductive impacts on healthy cells. immunosuppression and attendant increased risks of infection_ and many other adverse health conditions that attend the rigors and insults &conventional cancer 35 therapy.
Despite considerable advances in detection and treatment of cancer over the past several decades. conventional treatments like surgery-, chemotherapy and radiation often achieve only modest improvements in survival, while imposing significant adverse impacts on quality of life¨raising questions about cost-effectiveness and overall clinical benefits of such treatments.
In view of the foregoing there persists a dire and compelling need in the medical arts for alternative tools and methods to prevent, treat and clinically manage cancer.
Glioblastoma (GUM) is a high-grade cancer of the central nervous system (CNS) characterized by a highly invasive and treatment resistant phenotype. Patients almost always relapse after an either initially successful surgical resection with or without cherno- and radiotherapy (Ishiuchi et al, 2007). GUM tumors often exhibit resistance to chemotherapy and/or radiotherapy, which resistance may be acquired during a course of treatment (Ishiuchi et al, 2007).
Ternozolomide (TM7.) is a DNA methylating agent that is the current standard of care drug for treating GUM. TM/ mediates anti-cancer effects through genotoxie activity_ and is etTective in GBM treatment due in part to the drug's ability to bypass the blood-brain barrier (BBB) (Prasad et al. 2011). Unfortunately, TM/. shows limited efficacy for long-term treatment of GUM, and many patients appear to be refractory to TMZ treatment.
While considerable research has been attempted to elucidate the pathophysiology of OBM, a vast majority of drugs tested against GUM are unable to pass the BBB to yield sufficient drug levels in the brain to mediate anti-cancer effects (Liu et al.
2015).
Previous reports have suegested a role for glutamate in the proliferation and migration of glioma cells_ in a manner similar to glutamate function in neuronal development (Rzeski et al, 2001: Ishiuchi et al. 2002). Tumors of the CNS that release glutamate may cause eytotoxieity and cell death in neighboring neurons. which is postulated to facilitate cancer invasion into neighboring tissues (Ttikano et al_ 2001). Glutamate positive tumors may also grow at an enhanced rate. potentially implicating glutamate signaling as an important mechanism in the etiology of GUM (Takano et al. 2001).
Among many types of known glutamate receptors ((iRs). the AM PA-type glutamate receptor (AMPAR) may be overexpressed in certain types of cancer, including some forms of CNS cancers (Liu eta!, 2015) and non-CNS cancers (Steptilak et al, 2007:
Herner et al. 2011:
Romeling et al. 2014: Hu et al_ 2014). AMPAR activation may be linked to increased cancer cell invasiveness (Pia et al_ 2008). proliferation. andior activation of the 113K/AktlinTOR
signaling axis (Ishiuchi et al. 2007). The 1313K/A ktimIOR signaling axis has been implicated
EMPLOYING AMPA RECEPTOR ANTAGONISTS
TO TREAT GLIOBLASTOMA AND OTHER CANCERS
5 Technical Field The invention relates to drugs and clinical methods tor treating cancer in mammalian subjects. More specifically the invention relates to treating dioblastoma and other cancers that are positive for expression of AMPA-receptors.
10 Cross-Reference To Related Applications This application is related to and claims the priority benefit of prior US
Provisional Patent Application No. 62/703.952. filed July 27. 2018. and prior US
Provisional Patent Application No. 62/796.032. tiled January 23. 2019. each incorporated herein by reference in its entirety for all purposes.
Background of the Invention Cancer remains a principal mortality risk in human populations, with available drugs and treatment methods falling well short of goals to effectively treat and manage all forms of cancer in diverse patients. Today cancer persists as the second leading cause of death in the United States and in other developed nations. The US
National Cancer Institute (NCI) reported 8.2 million cancer-related deaths worldwide and 14.1 million new cases diagnosed in 2012. New cancer diagnoses are projected to rise globally to roughly 24 million by 2030.
According to current NCI statistics. an estimated 1.735.350 new eases of cancer will have been diagnosed and 609.640 cancer deaths tolled in the US for the year 2018.
The economic burdens of diagnosing and treating cancer on healthcare systems around the world arc enormous. Ns ith estimated national expenses for cancer care in the United States in 2017 approaching $150 billion. Cancer health costs will continue to rise as mean population age and cancer prevalence increase, and more expensive treatments are adopted as standards of care.
Conventional treatments for cancer typically involve a combination of surgery.
chemotherapy, radiation and hormonal therapy. Each of these treatment modalities imposes significant morbidity and added risks, tbr example adverse metabolic and reproductive impacts on healthy cells. immunosuppression and attendant increased risks of infection_ and many other adverse health conditions that attend the rigors and insults &conventional cancer 35 therapy.
Despite considerable advances in detection and treatment of cancer over the past several decades. conventional treatments like surgery-, chemotherapy and radiation often achieve only modest improvements in survival, while imposing significant adverse impacts on quality of life¨raising questions about cost-effectiveness and overall clinical benefits of such treatments.
In view of the foregoing there persists a dire and compelling need in the medical arts for alternative tools and methods to prevent, treat and clinically manage cancer.
Glioblastoma (GUM) is a high-grade cancer of the central nervous system (CNS) characterized by a highly invasive and treatment resistant phenotype. Patients almost always relapse after an either initially successful surgical resection with or without cherno- and radiotherapy (Ishiuchi et al, 2007). GUM tumors often exhibit resistance to chemotherapy and/or radiotherapy, which resistance may be acquired during a course of treatment (Ishiuchi et al, 2007).
Ternozolomide (TM7.) is a DNA methylating agent that is the current standard of care drug for treating GUM. TM/ mediates anti-cancer effects through genotoxie activity_ and is etTective in GBM treatment due in part to the drug's ability to bypass the blood-brain barrier (BBB) (Prasad et al. 2011). Unfortunately, TM/. shows limited efficacy for long-term treatment of GUM, and many patients appear to be refractory to TMZ treatment.
While considerable research has been attempted to elucidate the pathophysiology of OBM, a vast majority of drugs tested against GUM are unable to pass the BBB to yield sufficient drug levels in the brain to mediate anti-cancer effects (Liu et al.
2015).
Previous reports have suegested a role for glutamate in the proliferation and migration of glioma cells_ in a manner similar to glutamate function in neuronal development (Rzeski et al, 2001: Ishiuchi et al. 2002). Tumors of the CNS that release glutamate may cause eytotoxieity and cell death in neighboring neurons. which is postulated to facilitate cancer invasion into neighboring tissues (Ttikano et al_ 2001). Glutamate positive tumors may also grow at an enhanced rate. potentially implicating glutamate signaling as an important mechanism in the etiology of GUM (Takano et al. 2001).
Among many types of known glutamate receptors ((iRs). the AM PA-type glutamate receptor (AMPAR) may be overexpressed in certain types of cancer, including some forms of CNS cancers (Liu eta!, 2015) and non-CNS cancers (Steptilak et al, 2007:
Herner et al. 2011:
Romeling et al. 2014: Hu et al_ 2014). AMPAR activation may be linked to increased cancer cell invasiveness (Pia et al_ 2008). proliferation. andior activation of the 113K/AktlinTOR
signaling axis (Ishiuchi et al. 2007). The 1313K/A ktimIOR signaling axis has been implicated
2 in chemotherapy- resistance in GBMõ and available drugs reported to disrupt this pathway, such as raparnyein. do not penetrate the BBB. GUM cancer stern cells (suspected to be capable of re-establishing tumors after ablation with surgery, chemotherapy or radiotherapy) may express strikingly high amounts of functional AMPARs (Oh eta!, 2012).
In view of the foregoing, a compelling need exists in the art for new drugs and therapeutic methods for treating cancer. Related needs are unmet for new drugs for treating refractory or treatment-resistant forms of cancer, including cancers of the CNS. For CNS
cancers, particularly brain cancers such as Cif3M. there is a particularly urgent need for anti-cancer drugs capable of transiting the BBB to yield effective drug concentrations within protected CNS compartments. most notably within the brain.
Summary of Exemplar\ Embodiments of the Invention The instant invention satisfies the foregoing needs and fulfills additional objects and advantages by providing novel AMPAR antagonist drugs effective to treat AMPAR
positive cancers and AMPAR dependent cancers_ including AM PAR positive and AMPAR
dependent cancers of the central nervous system (CNS). In exemplary,' embodiments the invention provides compositions and methods employing a novel anti-cancer drug.
Perampanel (PMP) [2-(2-oxo-1-pheny1-5-pyridin-2-y1-1.2-dihydropyridin-3-y1) benzonitrile], heretofore reported for limited clinical use as an antispasmodic drug.
AMPA receptor antagonists have been investigated for antiseizure activity both preclinically and clinically, with mixed success. The prototypical competitive AMPA
receptor antagonist 2.3-dihydroxy--6-nitro-7-sulfamoyl-benzoll1 quinoxaline (NBOX) showed activity in maximal electroshock (M NS) and pentylenetetnizole (PTl)--induced seizure models (Yamaguchi et al.. 1993). but has poor solubility. resulting in precipitation in the kidney at therapeutic plasma levels. Derivatives of NBOX with polar constituents have shown improved solubility, but these molecules exhibit reduced blood¨brain barrier (13B13) penetration (Weiser, 2005). Prototypical noncompetifive AMPA receptor antagonists. such as 2.3-benzodiazepine-type compounds. have shown weak in vitro efficacy compared with competitive antagonists (Weiser. 2005). Talampanel. a recently developed noncompetitive AMPA receptor antagonist. has been evaluated in a number of clinical trials (I
lowes ez. Bell, 2007). but has a relatively short half-life militating- against its potential clinical utility (Langan et al., 2003). More recently. Steinhoff et al.. 2013. reported beneficial activity of Peramplanelõ a noncompetitive. selective AMPA receptor antagonist, as an antiepileptic drug undergoing clinical study for refractory partial-onset seizures.
In view of the foregoing, a compelling need exists in the art for new drugs and therapeutic methods for treating cancer. Related needs are unmet for new drugs for treating refractory or treatment-resistant forms of cancer, including cancers of the CNS. For CNS
cancers, particularly brain cancers such as Cif3M. there is a particularly urgent need for anti-cancer drugs capable of transiting the BBB to yield effective drug concentrations within protected CNS compartments. most notably within the brain.
Summary of Exemplar\ Embodiments of the Invention The instant invention satisfies the foregoing needs and fulfills additional objects and advantages by providing novel AMPAR antagonist drugs effective to treat AMPAR
positive cancers and AMPAR dependent cancers_ including AM PAR positive and AMPAR
dependent cancers of the central nervous system (CNS). In exemplary,' embodiments the invention provides compositions and methods employing a novel anti-cancer drug.
Perampanel (PMP) [2-(2-oxo-1-pheny1-5-pyridin-2-y1-1.2-dihydropyridin-3-y1) benzonitrile], heretofore reported for limited clinical use as an antispasmodic drug.
AMPA receptor antagonists have been investigated for antiseizure activity both preclinically and clinically, with mixed success. The prototypical competitive AMPA
receptor antagonist 2.3-dihydroxy--6-nitro-7-sulfamoyl-benzoll1 quinoxaline (NBOX) showed activity in maximal electroshock (M NS) and pentylenetetnizole (PTl)--induced seizure models (Yamaguchi et al.. 1993). but has poor solubility. resulting in precipitation in the kidney at therapeutic plasma levels. Derivatives of NBOX with polar constituents have shown improved solubility, but these molecules exhibit reduced blood¨brain barrier (13B13) penetration (Weiser, 2005). Prototypical noncompetifive AMPA receptor antagonists. such as 2.3-benzodiazepine-type compounds. have shown weak in vitro efficacy compared with competitive antagonists (Weiser. 2005). Talampanel. a recently developed noncompetitive AMPA receptor antagonist. has been evaluated in a number of clinical trials (I
lowes ez. Bell, 2007). but has a relatively short half-life militating- against its potential clinical utility (Langan et al., 2003). More recently. Steinhoff et al.. 2013. reported beneficial activity of Peramplanelõ a noncompetitive. selective AMPA receptor antagonist, as an antiepileptic drug undergoing clinical study for refractory partial-onset seizures.
3 According to the surprising discoveries herein, peramplanel (PMP) has now been identified to possess novel and potent anti-cancer activity. Within the coin positions and methods of the invention. PMP. along with its active analogs and derivatives, and other selected AMPAR antagonists disclosed herein. potently inhibit AMPAR positive and 5 AMPAR dependent cancers, including CNS cancers such as GUM.
The invention provides novel compositions and methods for treating cancer using AMPAR antagonist compounds such as PMP to reduce or prevent the occurrence.
remission.
growth. severit_v and/or one or more adverse svmptom(s) of AMPA-receptor positive cancers in mammalian subjects, including humans. In illustrative embodiments. the AMPAR
10 antagonist comprises a PMP compound (including anti-cancer effective chemical analogs, derivatives, conjugates, solid crystalline forms. solvates and/or different salt forms of a PMP
compound). which is clinically effective as an anti-cancer agent to treat or prevent cancer in mammalian subjects. In exemplary embodiments. PMP is administered to a human patient presenting with an AMPAR positive cancer condition in a delivery mode, formulation and 15 dosage sufficient to alleviate one or more symptoms of the targeted cancer condition in the patient In certain embodiments the PMP compound is perampanel [2-(2-oxo-l-phenyl-5-pyridin-2-yl-I.2-dihydropyridin-3-y1) benzonitrile] formulated in a biologically acceptable composition for administration to a human subject.
20 In related embodiments. novel clinical methods are provided herein employing a peramplanel or related compound administered to a mammalian subject, wherein the peramplanel compound exerts oncolytie effects against a targeted cancer cell or tumor sufficient to kill a targeted cell or tumor. reduce size of a tumor. impair tumor growth.
prevent or reduce cancer invasiveness, reduce or delay cancer recurrence, and/or alleviate one 25 or more symptoms associated with the treated cancer condition.
In more detailed embodiments. peramplanel and related compounds are employed in effective anti-cancer methods for treating glioblastotna (GUM). The peramplanel compound is administered to a mammalian subject with current or prior diagnosis of (IBM
in a dosage Ibrin. amount and regimen sufficient to prevent or reduce the occurrence.
severity, recurrence 30 and/or related symptoms of GIIM in the subject. In related embodiments, pharmaceutical compositions and delivery methods are provided that yield surprisingly high therapeutic concentrations of the peramplanel compound in a CNS compartment of the subject. e.g., in the brain, yielding potent anti-CNS-cancer therapeutic effects.
The invention provides novel compositions and methods for treating cancer using AMPAR antagonist compounds such as PMP to reduce or prevent the occurrence.
remission.
growth. severit_v and/or one or more adverse svmptom(s) of AMPA-receptor positive cancers in mammalian subjects, including humans. In illustrative embodiments. the AMPAR
10 antagonist comprises a PMP compound (including anti-cancer effective chemical analogs, derivatives, conjugates, solid crystalline forms. solvates and/or different salt forms of a PMP
compound). which is clinically effective as an anti-cancer agent to treat or prevent cancer in mammalian subjects. In exemplary embodiments. PMP is administered to a human patient presenting with an AMPAR positive cancer condition in a delivery mode, formulation and 15 dosage sufficient to alleviate one or more symptoms of the targeted cancer condition in the patient In certain embodiments the PMP compound is perampanel [2-(2-oxo-l-phenyl-5-pyridin-2-yl-I.2-dihydropyridin-3-y1) benzonitrile] formulated in a biologically acceptable composition for administration to a human subject.
20 In related embodiments. novel clinical methods are provided herein employing a peramplanel or related compound administered to a mammalian subject, wherein the peramplanel compound exerts oncolytie effects against a targeted cancer cell or tumor sufficient to kill a targeted cell or tumor. reduce size of a tumor. impair tumor growth.
prevent or reduce cancer invasiveness, reduce or delay cancer recurrence, and/or alleviate one 25 or more symptoms associated with the treated cancer condition.
In more detailed embodiments. peramplanel and related compounds are employed in effective anti-cancer methods for treating glioblastotna (GUM). The peramplanel compound is administered to a mammalian subject with current or prior diagnosis of (IBM
in a dosage Ibrin. amount and regimen sufficient to prevent or reduce the occurrence.
severity, recurrence 30 and/or related symptoms of GIIM in the subject. In related embodiments, pharmaceutical compositions and delivery methods are provided that yield surprisingly high therapeutic concentrations of the peramplanel compound in a CNS compartment of the subject. e.g., in the brain, yielding potent anti-CNS-cancer therapeutic effects.
4 In other detailed embodiments. a peramplanel compound is administered with a secondary therapeutic agent in combinatorial Ibrinulations or coordinate treatment methods to yield desired therapeutic advantages. In exemplary embodiments, a peramplanel compound is coordinately administered with a second anti-cancer drug to treat cancer, whereby anti-
5 cancer efficacy is enhanced and/or adverse side effects are reduced. In one illustrative embodiment, peramplanel is coordinately administered with temozolomide (TMZ) to treat GBM, pancreatic cancer, or another form of cancer. In another embodiment, peramplanel is coordinately administered with eisplatin to treat an AMPAR positive cancer, for example an AMPAR positive pancreatic cancer. In other exemplary embodiments, peramplanel is 10 coordinately administered with hydroxyurea to treat an AMPAR positive cancer. In other embodiments, peramplanel is coordinately administered with Carmustine (BCNU) to treat an AMPAR positive cancer.
In related treatment methods a peramplanel compound is coordinately administered before or after a conventional cancer treatment. Ibr example surgery, chemotherapy or 15 radiation treatment, with or I.% ithout a secondary anti-cancer agent or other secondary therapeutic drug.
In other detailed aspects of the invention, methods and compositions arc provided employing a peramplanel compound to reduce oncogenic activity by disrupting a glutamate-induced cancer potentiation process (e.g.. glutamate-stimulated cancer cell proliferation.
20 tumor growth, cancer invasion or other cancer-potentiation activity).
In yet additional embodiments of the invention, AMPAR antagonist compounds are employed in novel clinical methods and compositions to treat lung cancers, breast cancers, pancreatic cancers, liver cancers. colorectal cancers and other forms and symptoms of cancer conditions in human subjects.
Brief Description of the Drawing5 Figure I is a related graph series documenting the effects of PMP on T98G GBM
cell viability. Dose-response curve of A) PMP on cell viability B) Interactions with PMP and TMZ. Data are presented as mean +/- SEM o12 or more independent experiments performed 30 in quadruplicate. ANOVA, P<0.00 I for PMP suggesting a significant dose-dependent response. *p<0.05, **p<0.01 t-test_ compared to vehicle-treated control or singular drug treatment. +p<0.05. king's synergy test, demonstrating significant synergistic interaction.
Figure 2 is a related graph series documenting the effects of PMP on Pane I
cell viability. Dose-response curve of: A) PMP on cell viability: B) Interactions with PMP and 3uM cisplatim C) Effects of glutamate on panel cell viability: and D) Interactions between glutamate and PMP. Data are presented as mean 4-/- SEM of 2 or more independent experiments performed in quadruplicate. ANOVA. P<0.00 I for PMP and glutamate, indicating a significant dose-dependent response. *p<0.05. **p<0.0 I. t-test, compared to vehicle-treated control or singular drug treatment. -hp<0.05, 4-Fp<0.01, king's synergy test, demonstrating significant synergistic interaction. *p<0.01. t-test, compared to viability of glutamate- or PMP-treated cells alone.
Haim! 3 is a flow chart illustrating seven candidate anti-cancer chemical derivatives (D I 4)7) of peramplanel (PMP), wherein PMP is modified according to known methods of conventional rational design chemistry, to yield new candidate compounds for testing to determine anti-cancer activity and other beneficial properties.
Detailed Description of Exemplary Embodiments of the Invention The invention provides AMPAR antagonist.. compounds exemplified by peramplanel (PMP), shown to be surprisingly effective in treating cancers. including CNS
cancers, in mammalian subjects. Among the discoveries presented here. peramplanel is shown to exert potent. direct oncolytic effects against cancer cells in assays accepted to predict clinical anti-cancer activity in human subjects. More specifically the examples below show that PMP
potently disables viability of CNS and non-CNS cancers. as demonstrated by direct oncolytic effects against glioblastorna (613M) and pancreatic cancer cells. Related studies Further evince that peramplanel exerts surprisingly potent_ additive or synergistic anti-cancer effects in coordinate use with other chemotherapeutic drugs.
The clinical methods and pharmaceutical compositions and formulations of the invention provide novel tools to treat, prevent and clinically manage a wide range of cancers in mammalian subjects, including humans. Any type and form of cancer occurring in humans and veterinary subjects may be amenable to treatment according to the teachings herein, including, but not limited to: central nervous system (CNS) cancers including various forms of brain cancer: lung cancer; prostate cancer: breast cancer: skin cancers_ for example melanoma: liver cancer: thyroid cancer: esophageal cancer: sarcomas: colon and rectal cancers: bladder cancer: gall bladder cancer: stomach cancer: renal cancer:
ovarian cancer:
uterine cancer: cervical cancer: non-I lodgkin's lymphoma: acute myelogenous leukemia (AML): acute lymphocytic leukemia: chronic lymphocytic leukemia (CU..):
my,eloma:
mesothelioma: pancreatic cancer. Hodgkin's disease: testicular cancer:
Waldenstrotn's disease: head/neck cancer: cancer oldie tongue. viral-induced malignancies (e.g., cancers
In related treatment methods a peramplanel compound is coordinately administered before or after a conventional cancer treatment. Ibr example surgery, chemotherapy or 15 radiation treatment, with or I.% ithout a secondary anti-cancer agent or other secondary therapeutic drug.
In other detailed aspects of the invention, methods and compositions arc provided employing a peramplanel compound to reduce oncogenic activity by disrupting a glutamate-induced cancer potentiation process (e.g.. glutamate-stimulated cancer cell proliferation.
20 tumor growth, cancer invasion or other cancer-potentiation activity).
In yet additional embodiments of the invention, AMPAR antagonist compounds are employed in novel clinical methods and compositions to treat lung cancers, breast cancers, pancreatic cancers, liver cancers. colorectal cancers and other forms and symptoms of cancer conditions in human subjects.
Brief Description of the Drawing5 Figure I is a related graph series documenting the effects of PMP on T98G GBM
cell viability. Dose-response curve of A) PMP on cell viability B) Interactions with PMP and TMZ. Data are presented as mean +/- SEM o12 or more independent experiments performed 30 in quadruplicate. ANOVA, P<0.00 I for PMP suggesting a significant dose-dependent response. *p<0.05, **p<0.01 t-test_ compared to vehicle-treated control or singular drug treatment. +p<0.05. king's synergy test, demonstrating significant synergistic interaction.
Figure 2 is a related graph series documenting the effects of PMP on Pane I
cell viability. Dose-response curve of: A) PMP on cell viability: B) Interactions with PMP and 3uM cisplatim C) Effects of glutamate on panel cell viability: and D) Interactions between glutamate and PMP. Data are presented as mean 4-/- SEM of 2 or more independent experiments performed in quadruplicate. ANOVA. P<0.00 I for PMP and glutamate, indicating a significant dose-dependent response. *p<0.05. **p<0.0 I. t-test, compared to vehicle-treated control or singular drug treatment. -hp<0.05, 4-Fp<0.01, king's synergy test, demonstrating significant synergistic interaction. *p<0.01. t-test, compared to viability of glutamate- or PMP-treated cells alone.
Haim! 3 is a flow chart illustrating seven candidate anti-cancer chemical derivatives (D I 4)7) of peramplanel (PMP), wherein PMP is modified according to known methods of conventional rational design chemistry, to yield new candidate compounds for testing to determine anti-cancer activity and other beneficial properties.
Detailed Description of Exemplary Embodiments of the Invention The invention provides AMPAR antagonist.. compounds exemplified by peramplanel (PMP), shown to be surprisingly effective in treating cancers. including CNS
cancers, in mammalian subjects. Among the discoveries presented here. peramplanel is shown to exert potent. direct oncolytic effects against cancer cells in assays accepted to predict clinical anti-cancer activity in human subjects. More specifically the examples below show that PMP
potently disables viability of CNS and non-CNS cancers. as demonstrated by direct oncolytic effects against glioblastorna (613M) and pancreatic cancer cells. Related studies Further evince that peramplanel exerts surprisingly potent_ additive or synergistic anti-cancer effects in coordinate use with other chemotherapeutic drugs.
The clinical methods and pharmaceutical compositions and formulations of the invention provide novel tools to treat, prevent and clinically manage a wide range of cancers in mammalian subjects, including humans. Any type and form of cancer occurring in humans and veterinary subjects may be amenable to treatment according to the teachings herein, including, but not limited to: central nervous system (CNS) cancers including various forms of brain cancer: lung cancer; prostate cancer: breast cancer: skin cancers_ for example melanoma: liver cancer: thyroid cancer: esophageal cancer: sarcomas: colon and rectal cancers: bladder cancer: gall bladder cancer: stomach cancer: renal cancer:
ovarian cancer:
uterine cancer: cervical cancer: non-I lodgkin's lymphoma: acute myelogenous leukemia (AML): acute lymphocytic leukemia: chronic lymphocytic leukemia (CU..):
my,eloma:
mesothelioma: pancreatic cancer. Hodgkin's disease: testicular cancer:
Waldenstrotn's disease: head/neck cancer: cancer oldie tongue. viral-induced malignancies (e.g., cancers
6 induced by SV40 virus), and other candidate types and forms of cancers that will be apparent to skilled artisans.
Subjects amenable to treatment mak have cancer of any stage of development and etiology, including, but not limited to, cancers marked by rapid increases in 5 cellular/histological abnormalities and/or elevated tumor marker expression in biopsies or blood samples_ rapid tumor proliferation and/or growth_ metastasis_ among other disease progression indicators, up to and including stage III and stage IV cancers, even refractory stage III and IV shown to be -treatment resistant cancers' (e.g., to effectively subjects with cancers, such as glioblastoma, persisting or relapsing after ineffective, conventional anti-10 cancer treatment(s) (e.g._ surgery. radiation and/or chemotherapy)). In exemplary embodiments of the invention an effective AMPAR antagonist drug such as PMP
effectively prevents or treats (i.e., reduces the severity, progression and/or adverse side effects of) cancer in treatment resistant subjects. defined as subjects presenting after one or more rounds of conventional oneotherapy (e.g.. chemotherapy. radiation.. surgery and/or hormonal therapy), 15 with actively progressing or unstable metastatic disease. In other embodiments the compositions and methods of the invention are useful for treating other "refractory- patients who ma k not otherwise tolerate or be lit for conventional cancer treatments such as chemotherapy.
Certain cancer types and disease conditions are contemplated herein to be particularly 20 amenable to treatment using the AMPAR antagonist drugs and methods of the invention. In certain embodiments. the AMPAR antagonist drugs and methods of the invention are particularly effective against -AMPAR dependent" cancers. As used herein the term -AMPAR dependent refers to cancers that distinctly overexpress AMPA receptors, or whose appearance. growth, and/or disease progression may otherwise be determined to be AMPAR-25 dependent. In more detailed aspects. "AMPAR-dependent" cancers are not limited to cancers whose occurrence, persistence or progression require abnormally elevated AMPAR
receptor expression or activity, indeed they may include cancers with normal or even subnormal expression of A MPARs. which through disease-associated changes in AMPAR
structure or function_ or any other disease-associated change affecting AMPAR metabolism or pathology.
30 are particularly susceptible to AMPA receptor interference or blockade using PMP or other candidate AMPAR drugs of the invention.
In this context, the use of AMPAR antagonist drugs exemplified by PMP, according to the teachings herein. effectively treats or prevents a wide range of cancers contemplated to represent -AMPAR-dependent cancersi including but not limited to brain cancer.
breast
Subjects amenable to treatment mak have cancer of any stage of development and etiology, including, but not limited to, cancers marked by rapid increases in 5 cellular/histological abnormalities and/or elevated tumor marker expression in biopsies or blood samples_ rapid tumor proliferation and/or growth_ metastasis_ among other disease progression indicators, up to and including stage III and stage IV cancers, even refractory stage III and IV shown to be -treatment resistant cancers' (e.g., to effectively subjects with cancers, such as glioblastoma, persisting or relapsing after ineffective, conventional anti-10 cancer treatment(s) (e.g._ surgery. radiation and/or chemotherapy)). In exemplary embodiments of the invention an effective AMPAR antagonist drug such as PMP
effectively prevents or treats (i.e., reduces the severity, progression and/or adverse side effects of) cancer in treatment resistant subjects. defined as subjects presenting after one or more rounds of conventional oneotherapy (e.g.. chemotherapy. radiation.. surgery and/or hormonal therapy), 15 with actively progressing or unstable metastatic disease. In other embodiments the compositions and methods of the invention are useful for treating other "refractory- patients who ma k not otherwise tolerate or be lit for conventional cancer treatments such as chemotherapy.
Certain cancer types and disease conditions are contemplated herein to be particularly 20 amenable to treatment using the AMPAR antagonist drugs and methods of the invention. In certain embodiments. the AMPAR antagonist drugs and methods of the invention are particularly effective against -AMPAR dependent" cancers. As used herein the term -AMPAR dependent refers to cancers that distinctly overexpress AMPA receptors, or whose appearance. growth, and/or disease progression may otherwise be determined to be AMPAR-25 dependent. In more detailed aspects. "AMPAR-dependent" cancers are not limited to cancers whose occurrence, persistence or progression require abnormally elevated AMPAR
receptor expression or activity, indeed they may include cancers with normal or even subnormal expression of A MPARs. which through disease-associated changes in AMPAR
structure or function_ or any other disease-associated change affecting AMPAR metabolism or pathology.
30 are particularly susceptible to AMPA receptor interference or blockade using PMP or other candidate AMPAR drugs of the invention.
In this context, the use of AMPAR antagonist drugs exemplified by PMP, according to the teachings herein. effectively treats or prevents a wide range of cancers contemplated to represent -AMPAR-dependent cancersi including but not limited to brain cancer.
breast
7 cancer. colorectal cancer. hepatocellular cancer_ leukemia, melanoma, lung cancer, pancreatic cancer. renal cancer. and other candidate cancer types or cases determined to be clinically susceptible to AMPAR interference or blockade by PMP or another useful AMPAR
antagonist.
5 Each of the anti-cancer methods of the invention involves administration of a suitable, effective dosage amount of PMP or another useful AMPAR antagonist to a subject.
Typically, an effective amount will comprise an amount of the active compound (e.g.. PMP) which is therapeutically effective. in a single or multiple unit dosage form.
over a specified period of therapeutic intervention, to measurably alleviate the targeted cancer condition.
10 Within exemplary embodiments. PMP is used as the sole or primary active drug. In other embodiments. an intermediary or precursor compound to PMP. or a rationally-designed analog or derivative of PMP (i.e., a related compound having close structural and functional similarity to PMP) is employed. The PMP or other effective AMPAR antagonist is typically formulated in a pharmaceutical composition NN ith one or more pharmaceutically acceptable 15 carriers, excipients, vehicles. emulsifiers, stabilizers_ preservatives, buffers, and/or other additives that may enhance stability, delivery. absorption, half-life, efficacy, phannacokinetics, and/or pharmacodynamics, reduce adverse side effects, or provide other advantages for pharmaceutical use.
Anti-cancer effective dosage amounts of PMP and other effective. anti-cancer 20 AMPAR antagonists of the invention will be readily determined by those of ordinary skill in the art, depending on clinical and patient-specific factors. Suitable effective unit dosage amounts of the active compounds for administration to mammalian subjects.
including humans. may range from a minimum daily dose of 1-2 am up to a maximum prospective dose between about 200-500 or 300-1.000 mg/day. or greater. In certain embodiments.
the anti-25 cancer effective dose is between about 2 mg-200 mu/day, in other embodiments between about 20-400 mg/day. 50-500 mg/day. 200-600 mg/day. or another anti-cancer effective dose or dosage range that can be adjusted based on patient specific factors to optimize efficacy and minimize adverse side effects. The PMP or other AMPAR antagonist may be administered in a single dose, or in the form of a multiple periodic dosing protocol_ for example in a dosing 30 regimen comprising from I to 5. or 2-3 doses administered per day. per week, or per month.
The amount. timing and mode of delivery of the anti-cancer compositions of the invention will be routinely adjusted on an individual basis, depending on such factors as patient weight, age. gender, and condition of the individual, the acuteness of the subject's disease and severity symptoms_ whether the administration is prophylactic or therapeutic,
antagonist.
5 Each of the anti-cancer methods of the invention involves administration of a suitable, effective dosage amount of PMP or another useful AMPAR antagonist to a subject.
Typically, an effective amount will comprise an amount of the active compound (e.g.. PMP) which is therapeutically effective. in a single or multiple unit dosage form.
over a specified period of therapeutic intervention, to measurably alleviate the targeted cancer condition.
10 Within exemplary embodiments. PMP is used as the sole or primary active drug. In other embodiments. an intermediary or precursor compound to PMP. or a rationally-designed analog or derivative of PMP (i.e., a related compound having close structural and functional similarity to PMP) is employed. The PMP or other effective AMPAR antagonist is typically formulated in a pharmaceutical composition NN ith one or more pharmaceutically acceptable 15 carriers, excipients, vehicles. emulsifiers, stabilizers_ preservatives, buffers, and/or other additives that may enhance stability, delivery. absorption, half-life, efficacy, phannacokinetics, and/or pharmacodynamics, reduce adverse side effects, or provide other advantages for pharmaceutical use.
Anti-cancer effective dosage amounts of PMP and other effective. anti-cancer 20 AMPAR antagonists of the invention will be readily determined by those of ordinary skill in the art, depending on clinical and patient-specific factors. Suitable effective unit dosage amounts of the active compounds for administration to mammalian subjects.
including humans. may range from a minimum daily dose of 1-2 am up to a maximum prospective dose between about 200-500 or 300-1.000 mg/day. or greater. In certain embodiments.
the anti-25 cancer effective dose is between about 2 mg-200 mu/day, in other embodiments between about 20-400 mg/day. 50-500 mg/day. 200-600 mg/day. or another anti-cancer effective dose or dosage range that can be adjusted based on patient specific factors to optimize efficacy and minimize adverse side effects. The PMP or other AMPAR antagonist may be administered in a single dose, or in the form of a multiple periodic dosing protocol_ for example in a dosing 30 regimen comprising from I to 5. or 2-3 doses administered per day. per week, or per month.
The amount. timing and mode of delivery of the anti-cancer compositions of the invention will be routinely adjusted on an individual basis, depending on such factors as patient weight, age. gender, and condition of the individual, the acuteness of the subject's disease and severity symptoms_ whether the administration is prophylactic or therapeutic,
8 prior treatment history (including e.g., any prior history and responsiveness to chemotherapy or other cancer treatment treatment) and on the basis of other factors known to effect drug delivery, absorption, phannacokinetics and efficacy. An effective dose or multi-dose treatment regimen for the instant AM PAR antagonist formulations will ordinarily be selected to approximate a minimal dosing regimen necessary and sufficient to substantially prevent or alleviate the cancer condition, and/or to substantially prevent or alleviate one or more symptoms associated with that condition.
A dosage and administration protocol will often include repeated dosing therapy over a course of several days or even one or more weeks, up to several months. or even a year or more. An effective treatment regime may also involve prophylactic dosage administered on a daily or multi-dose per day basis lasting over a course of days_ weeks, months or even a year or more.
Various assays and pre-clinical and clinical model systems can be readily employed to determine therapeutic effectiveness of the anti-cancer compositions and methods invention.
For example. these may detect/monitor a decrease in overt symptoms, such as pain (e.g., as measured using any of a variety of pain scales including. but not limited to.
the Visual Analog Seale. McGill Pain Questionnaire._ Descriptor Differential Scale. Faces Pain Scale, Verbal Rating Scale. Simple Descriptive Pain Scale. Numerical Pain Scale (N
PS). or Dolorimeter Pain Index). More detailed detection/monitoring may document, for example, a decrease in circulating tumor cells (CFCs). reduction in tumor size. collapse or disappearance of tumors. softening of tumors. liquefaction ofttimors, or a decrease in cytological or histochemical cancer markers, among many other conventional diagnostic indicia of cancer disease stasis. progression and/or remission.
Effectiveness of the anti-cancer methods and compositions of the invention are generally demonstrated by a decrease in incidence, severity and/or associated symptoms of cancer. which will typically involve a decrease of 5%. 10%. 25%. 30%. 50%, 75%. 90% or more in comparison to incidence/levels of the same diagnosed indicator/state, or attendant symptom(s) in suitable control subjects (or compared to known baseline or median data for like, treated or untreated subjects). For example. PMP-treated cancer patients will often exhibit a decrease in number or size of targeted tumors, a decrease in circulating tumor cells (CTCs) or Cancer Stem Cells (C'S('s) in successive blood assays. and/or a decrease in one or more tumor-associated cytological. histoehemical or blood markers, during a course of treatment, of from 25%-30%. 50%. 75% or higher. 90% and up to total absence of the disease indicator(s) to a limit of detectability associated with the employed assay(s). Monitoring for
A dosage and administration protocol will often include repeated dosing therapy over a course of several days or even one or more weeks, up to several months. or even a year or more. An effective treatment regime may also involve prophylactic dosage administered on a daily or multi-dose per day basis lasting over a course of days_ weeks, months or even a year or more.
Various assays and pre-clinical and clinical model systems can be readily employed to determine therapeutic effectiveness of the anti-cancer compositions and methods invention.
For example. these may detect/monitor a decrease in overt symptoms, such as pain (e.g., as measured using any of a variety of pain scales including. but not limited to.
the Visual Analog Seale. McGill Pain Questionnaire._ Descriptor Differential Scale. Faces Pain Scale, Verbal Rating Scale. Simple Descriptive Pain Scale. Numerical Pain Scale (N
PS). or Dolorimeter Pain Index). More detailed detection/monitoring may document, for example, a decrease in circulating tumor cells (CFCs). reduction in tumor size. collapse or disappearance of tumors. softening of tumors. liquefaction ofttimors, or a decrease in cytological or histochemical cancer markers, among many other conventional diagnostic indicia of cancer disease stasis. progression and/or remission.
Effectiveness of the anti-cancer methods and compositions of the invention are generally demonstrated by a decrease in incidence, severity and/or associated symptoms of cancer. which will typically involve a decrease of 5%. 10%. 25%. 30%. 50%, 75%. 90% or more in comparison to incidence/levels of the same diagnosed indicator/state, or attendant symptom(s) in suitable control subjects (or compared to known baseline or median data for like, treated or untreated subjects). For example. PMP-treated cancer patients will often exhibit a decrease in number or size of targeted tumors, a decrease in circulating tumor cells (CTCs) or Cancer Stem Cells (C'S('s) in successive blood assays. and/or a decrease in one or more tumor-associated cytological. histoehemical or blood markers, during a course of treatment, of from 25%-30%. 50%. 75% or higher. 90% and up to total absence of the disease indicator(s) to a limit of detectability associated with the employed assay(s). Monitoring for
9 effective cancer prevention and treatment of the invention can employ any of a vast array conventional detection and monitoring tools and indicia. as will be apparent to those skilled in the art. For example. CTC monitoring using blood samples of' patients can utilize flow cytometry. immunobead capture. fluorescence microscopy, standard and density 5 centrifugation. cell culturing, and immunocytoeltemistry . Similarly, tumor monitoring can employ x-ray. MRI_ CT or PET scans. among other methods and tools. For economy these and other routine, well-known cancer disease detection and monitoring technologies will not be reiterated here.
As noted above, exemplary embodiments of the invention employ peramplanel (PMP)
As noted above, exemplary embodiments of the invention employ peramplanel (PMP)
10 as an anti-cancer effective AMPAR antagonist compound. Perampanel is structurally distinct from other AM PAR antagonists, which as a group show a great deal of structural diversity (for example. as illustrated in Table 1 comparing the structure of PMP to two other AMPAR
antagonists, Telampanel and NRQX.
15 Table I Diverse Chemical Structure of AMP.AR
Antagonists tIt4( o Nit 0=S =0 Fr N11., N
NBQX
CN
<
-1\
( Perampanet cr.) Tata m panel According to the discoveries herein. PMP potently reduces or prevents the occurrence, remission, growth and/or severity of targeted cancers in mammalian subjects, including humans. In certain embodiments. PMP is effective to prevent or treat (including to reduce one or more adverse symptom(s) on_ an AMPAR positive cancer in a human cell 5 population, tissue, organ or whole patient. For clinical use, effective anti-cancer compositions may comprise a prototypical PMP compound [2-(2-oxo-l-pheny1-5-pyridin-2-y1-1.2-dihydropyridin-3-y1) benzonitri le]. or any effective prodrug.
metabolite, analog.
derivative, conjugate, solid crystalline lbrrn, solvate and/or advantageous salt form of PMP
shown to be clinically effective as an anti-cancer agent.
10 In view of the disclosed potent anti-cancer effects of peramplanel (PMP). the invention further provides various chemical analogs and derivatives of PMP
that actively treat or prevent cancer_ and in certain cases provide additional clinical advantages, for example improved solubilit). enhanced blood-brain barrier penetration, prolonged half-life.
increased AM PAR antagonist activity, among other functional improvements.
15 Figure 3 provides a flow chart illustrating seven candidate anti-cancer chemical derivatives (Dl-D7) of peramplanel (PMP) contemplated for anti-cancer testing within the clinical methods herein. The illustrated compounds. Dl-D7 can be readily produced. along with many additional PMP analogs and derivatives, employing known methods of conventional rational design chemistry. Such routine design and synthesis efforts will yield a 20 diverse array of new candidate compounds for testing within the methods of the invention, to determine anti-cancer activity and other beneficial properties. In general terms. each of the available R groups identified within or attached to each of the aromatic rings of PMP can be altered (e.g.. by chemical deletion, substitution or addition) to yield new candidate PMP
derivative drugs as described. The exemplary derivatives shown in Figure 3 ¨
PMP DI may 25 be designed. tested and selected to have increased solubility. improved half-life, better delivery or penetration to desired targets or compartments (e.g.. to deliver an effective dose within a tumor mass, to transit the blood brain barrier (BBB) in anti-cancer effective amounts. to survive first pass metabolism and transport to a target organ in effective plasma concentration. etc.). According to the illustrative embodiments here. PMP
derivatives 1)2, 30 D3 and D4 are designed to have more hydrophilic character. whereby they will have improved BBB penetration and accumulate to an effective concentration greater in the CNS
to mediate clinical benefits of treating and/or preventing CNS related cancers such as GBM.
PMP D5 is designed to provide increased solubility for improved drug delivery.
bioavailability and clinical efficacy. PMP 1)6 is an exemplar prodrug (a glycine ester) of
antagonists, Telampanel and NRQX.
15 Table I Diverse Chemical Structure of AMP.AR
Antagonists tIt4( o Nit 0=S =0 Fr N11., N
NBQX
CN
<
-1\
( Perampanet cr.) Tata m panel According to the discoveries herein. PMP potently reduces or prevents the occurrence, remission, growth and/or severity of targeted cancers in mammalian subjects, including humans. In certain embodiments. PMP is effective to prevent or treat (including to reduce one or more adverse symptom(s) on_ an AMPAR positive cancer in a human cell 5 population, tissue, organ or whole patient. For clinical use, effective anti-cancer compositions may comprise a prototypical PMP compound [2-(2-oxo-l-pheny1-5-pyridin-2-y1-1.2-dihydropyridin-3-y1) benzonitri le]. or any effective prodrug.
metabolite, analog.
derivative, conjugate, solid crystalline lbrrn, solvate and/or advantageous salt form of PMP
shown to be clinically effective as an anti-cancer agent.
10 In view of the disclosed potent anti-cancer effects of peramplanel (PMP). the invention further provides various chemical analogs and derivatives of PMP
that actively treat or prevent cancer_ and in certain cases provide additional clinical advantages, for example improved solubilit). enhanced blood-brain barrier penetration, prolonged half-life.
increased AM PAR antagonist activity, among other functional improvements.
15 Figure 3 provides a flow chart illustrating seven candidate anti-cancer chemical derivatives (Dl-D7) of peramplanel (PMP) contemplated for anti-cancer testing within the clinical methods herein. The illustrated compounds. Dl-D7 can be readily produced. along with many additional PMP analogs and derivatives, employing known methods of conventional rational design chemistry. Such routine design and synthesis efforts will yield a 20 diverse array of new candidate compounds for testing within the methods of the invention, to determine anti-cancer activity and other beneficial properties. In general terms. each of the available R groups identified within or attached to each of the aromatic rings of PMP can be altered (e.g.. by chemical deletion, substitution or addition) to yield new candidate PMP
derivative drugs as described. The exemplary derivatives shown in Figure 3 ¨
PMP DI may 25 be designed. tested and selected to have increased solubility. improved half-life, better delivery or penetration to desired targets or compartments (e.g.. to deliver an effective dose within a tumor mass, to transit the blood brain barrier (BBB) in anti-cancer effective amounts. to survive first pass metabolism and transport to a target organ in effective plasma concentration. etc.). According to the illustrative embodiments here. PMP
derivatives 1)2, 30 D3 and D4 are designed to have more hydrophilic character. whereby they will have improved BBB penetration and accumulate to an effective concentration greater in the CNS
to mediate clinical benefits of treating and/or preventing CNS related cancers such as GBM.
PMP D5 is designed to provide increased solubility for improved drug delivery.
bioavailability and clinical efficacy. PMP 1)6 is an exemplar prodrug (a glycine ester) of
11 PMP D5. which will be rapidly hydrolyzed into PMP DS in the blood by plasma glycine esterases. thus providing the contemplated prodrug benefits in addition to increased solubility. PMP D7 and 138 are likewise more hydrophilic derivatives of PMP
which will penetrate the BBB and accumulate in effective concentrations for anti-cancer drug effects in 5 the CNS.
In other exemplary PMP derivative and analog design. each R group may be modified to a same. or different. derivative or analog R group identity. Rational design chemical alterations to PMP can include alterations wherein an original PMP R group is altered to a new structural identity selected from, for example: a substituted or unsubstituted lower 10 hydrocarbon including an alkyl. alkenyl. alkanoyl. alkynyl. aryl. aroyl.
aralkyl, alkylamino, aryloxy, hydrogen, carboxyl. nitro, thioalkoxy,-. thioaryloxy. thiol, cycloalkenyl cycloalkyl, heterocycloalkyl. heteroaryl. aralkyl, amino acid. peptide_ dye. fitiorophore, carbohydrate or polypeptide; a hydrogen. hydroxyl. sulfyhydryl, fluorine, methyl, ethyl, propyl, benzyl, 2-bromovinyl amino. hydroxymethyl. methoxy. halogen. pseudohalogen. cyano, carboxyl, 15 nitro_ thioalkoxy. thioaryloxy, or thiol: a substituted or unsubstituted lower hydrocarbon containing 1 to 20 carbons such as alkoxyearbonyl. allkoxycarbonylamino.
amino, amino acid. aminocarbonyl. arninocarbonyloxy. aralkyl, aryloxy, carboxyl.
cycloalkenyl. alkyl, cycloalkyl, heterocycloalkyl. aryl. heteroaryl. aralkyl. amino acid, peptide, dye, tluorophore, carbohydrate or polypeptide: a heteroatom such as oxygen, sulfur or nitrogen:
and/or an 20 integral member of a new 5. or 6. member exocyclic ring structure, among other alterations where feasible to Yield a viable test candidate derivative. In more detailed embodiments, one or more R group(s) of PMP can be modified to a hydrogen. hy-droxyl, sulfyhydryl. benzyl. 2-bromoyinyl amino, hydroxymethyl. methoxy. halogen. pseutiohalogen, cyano.
carboxyl, nitro, thioalkyl. thioaryl, thiol, substituted or unsubstituted hydrocarbons containing 1 to 20 25 carbons. alkoxy.icarbonyl. alkoxycarbonylamino. amino4 amino acid, aminocarbonyl, aminoearbonyloxy. aryloxy. carboxyl, cycloalkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl. substituted or unsubstituted heteroaryl. substituted or unsubstituted aralkyl. peptidyl. dye.
fluorophore.
carbohydrate or polypeptidyl. azido, nitrite. substituted benzoyl or hydroxyl substituted with 30 substituted or unsubstituted hydrocarbon containing 1 to 20 carbons_ and/or an alkanoyl of a main chain of 1 to 20 carbon atoms, among many other contemplated derivative changes obtainable and testable according to the teachings herein without undue experimentation.
Within additional aspects of the invention, combinatorial formulations and coordinate treatment methods are provided that employ an effective amount of PMP or another anti-
which will penetrate the BBB and accumulate in effective concentrations for anti-cancer drug effects in 5 the CNS.
In other exemplary PMP derivative and analog design. each R group may be modified to a same. or different. derivative or analog R group identity. Rational design chemical alterations to PMP can include alterations wherein an original PMP R group is altered to a new structural identity selected from, for example: a substituted or unsubstituted lower 10 hydrocarbon including an alkyl. alkenyl. alkanoyl. alkynyl. aryl. aroyl.
aralkyl, alkylamino, aryloxy, hydrogen, carboxyl. nitro, thioalkoxy,-. thioaryloxy. thiol, cycloalkenyl cycloalkyl, heterocycloalkyl. heteroaryl. aralkyl, amino acid. peptide_ dye. fitiorophore, carbohydrate or polypeptide; a hydrogen. hydroxyl. sulfyhydryl, fluorine, methyl, ethyl, propyl, benzyl, 2-bromovinyl amino. hydroxymethyl. methoxy. halogen. pseudohalogen. cyano, carboxyl, 15 nitro_ thioalkoxy. thioaryloxy, or thiol: a substituted or unsubstituted lower hydrocarbon containing 1 to 20 carbons such as alkoxyearbonyl. allkoxycarbonylamino.
amino, amino acid. aminocarbonyl. arninocarbonyloxy. aralkyl, aryloxy, carboxyl.
cycloalkenyl. alkyl, cycloalkyl, heterocycloalkyl. aryl. heteroaryl. aralkyl. amino acid, peptide, dye, tluorophore, carbohydrate or polypeptide: a heteroatom such as oxygen, sulfur or nitrogen:
and/or an 20 integral member of a new 5. or 6. member exocyclic ring structure, among other alterations where feasible to Yield a viable test candidate derivative. In more detailed embodiments, one or more R group(s) of PMP can be modified to a hydrogen. hy-droxyl, sulfyhydryl. benzyl. 2-bromoyinyl amino, hydroxymethyl. methoxy. halogen. pseutiohalogen, cyano.
carboxyl, nitro, thioalkyl. thioaryl, thiol, substituted or unsubstituted hydrocarbons containing 1 to 20 25 carbons. alkoxy.icarbonyl. alkoxycarbonylamino. amino4 amino acid, aminocarbonyl, aminoearbonyloxy. aryloxy. carboxyl, cycloalkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl. substituted or unsubstituted heteroaryl. substituted or unsubstituted aralkyl. peptidyl. dye.
fluorophore.
carbohydrate or polypeptidyl. azido, nitrite. substituted benzoyl or hydroxyl substituted with 30 substituted or unsubstituted hydrocarbon containing 1 to 20 carbons_ and/or an alkanoyl of a main chain of 1 to 20 carbon atoms, among many other contemplated derivative changes obtainable and testable according to the teachings herein without undue experimentation.
Within additional aspects of the invention, combinatorial formulations and coordinate treatment methods are provided that employ an effective amount of PMP or another anti-
12 cancer effective AM PAR antagonist compound or composition, and one or more secondary or adjunctive agent(s) combinatorially formulated or coordinately administered with the AMPAR antagonist compound or composition to yield an enhanced anti-cancer composition or method. Exemplary combinatorial formulations and coordinate treatment methods in this 5 context employa PMP compound in combination with the one or more secondary anti-cancer, anti-viral, and/or immune-stimulatory effective agents or drugs.
Exemplary combinatorial formulations and coordinate treatment methods of the invention employ PMP or another anti-cancer effective A M PAR antagonist compound or composition in combination with one or more secondary or adjunctive anti-cancer effective 10 agents. for example one or more chemotherapeutic agents. Employing general terminology for "chemotherapeutic drugs and adjunctive anti-cancer therapies", these secondary agents/therapies for use within the invention may include any anti-cancer or anti-proliferative agent. agents that destroy or -'reprograrn- cancer cells, agents that destroy blood vessels associated with neoplasms or hyperproliferative conditions and other classes of drugs 15 harmful to neoplastic cellular targets. In this regard. useful chemotherapeutics and adjunctive therapies for use within the invention include. but are not limited to:
(1) Tubulin depolyrnerizing agents like toxoids:
(2) DNA damaging agents and agents that inhibit DNA synthesis:
(3) Anti-metabolics:
20 (4) Anti-angiogenic agents and vascular disrupting agents (VDAs);
(5) Anti-cancer antibodies:
(6) Endocrine cancer therapies:
(7) Immuno-modulators;
(8) Ilistone deacetylase inhibitors:
25 (9) Inhibitors of signal transduction:
( 10) Inhibitors of heat shock proteins:
(11) Retinoids:
(12) Growth Factors and Modulators of growth factor receptors:
( 13) Anti-mitotic compounds:
30 (14) Anti-inflammatory agents such as COX inhibitors: and (15) Cell cycle regulators (eg, check point regulators and telomerase inhibitors).
In related embodiments. coordinate anti-cancer treatment methods of the invention can include coordinate administration of one or more anti-cancer AMPAR
antagonist
Exemplary combinatorial formulations and coordinate treatment methods of the invention employ PMP or another anti-cancer effective A M PAR antagonist compound or composition in combination with one or more secondary or adjunctive anti-cancer effective 10 agents. for example one or more chemotherapeutic agents. Employing general terminology for "chemotherapeutic drugs and adjunctive anti-cancer therapies", these secondary agents/therapies for use within the invention may include any anti-cancer or anti-proliferative agent. agents that destroy or -'reprograrn- cancer cells, agents that destroy blood vessels associated with neoplasms or hyperproliferative conditions and other classes of drugs 15 harmful to neoplastic cellular targets. In this regard. useful chemotherapeutics and adjunctive therapies for use within the invention include. but are not limited to:
(1) Tubulin depolyrnerizing agents like toxoids:
(2) DNA damaging agents and agents that inhibit DNA synthesis:
(3) Anti-metabolics:
20 (4) Anti-angiogenic agents and vascular disrupting agents (VDAs);
(5) Anti-cancer antibodies:
(6) Endocrine cancer therapies:
(7) Immuno-modulators;
(8) Ilistone deacetylase inhibitors:
25 (9) Inhibitors of signal transduction:
( 10) Inhibitors of heat shock proteins:
(11) Retinoids:
(12) Growth Factors and Modulators of growth factor receptors:
( 13) Anti-mitotic compounds:
30 (14) Anti-inflammatory agents such as COX inhibitors: and (15) Cell cycle regulators (eg, check point regulators and telomerase inhibitors).
In related embodiments. coordinate anti-cancer treatment methods of the invention can include coordinate administration of one or more anti-cancer AMPAR
antagonist
13 compounds with a secondary anti-cancer agent selected from az.acitidine.
bevacizumab.
bortezomib. capecitabine, cetuximab. clofarabine. dasatinib, decitabine, doeetaxel, emend.
erlotinib hydrochloride. exemestane_ fulvestrant. gefitinib. ueincitabine hydrochloride, irnati nib mesylate. imiquimod. lenalidomide. letrozole nelarabine.
oxaliplatin, paclitaxel, 5 docetaxel, paliferm in. panitumumab. pegaspargase_ pemetrexed di sodium, rituximab, sorafenib tosylate, sunitinib malate, tamoxifen citrate, targretin, temozolomide, thalidomide, and/or topotecan hydrochloride. Additional contemplated secondary anti-cancer effective agents in this context include. but are not limited to. interleukin-2.
interferon a. filgrasten_ G-CSF, epoetin alla, erythropoietin. oprelvekin.
trastuzumab, vorinostat. antibiotics, 10 coenzyme q. palladium lipoic complexes including, for example_ poly-MVAK.
antineoplastins, cartilage_ hydrazine sulfate; milk thistle, electrolytes such as calcium carbonate, magnesium carbonate. sodium bicarbonate_ and potassium bicarbonate;
oxidizing agents. including. but not limited to. cesium chloride, potassium chloride, potassium orotate and potassium aspartate: immunoulobulins, colostrum: and vitamin and mineral supplements, 15 including but not limited to. zinc chloride. magnesium chloride, pyridoxine, vitamin B- 12, B
complexes_ folic acid, sodium ascorbate_ and probiotics. Additional secondary therapies may include conventional chemotherapy, radiation therapy. and/or surgery.
In certain illustrative embodiments directed to treatment of glioblastorna (GBM), pancreatic cancer and other AMPAR-dependent types/forms of cancer. the AMP or other 20 AMPAR antagonist is coordinately administered with temozolomide (TMZ).
In related embodiments, the PMP or other AMPAR antagonist is coordinately administered with eisplatin to treat an AMPAR-dependent cancer, for example an AMPAR-positive pancreatic cancer. In other exemplary embodiments. an anti-cancer effective PMP or other AMPAR
antagonist compound is coordinately administered with hydroxyurea to treat an AMPAR
25 positive cancer. In other embodiments. the PMP or other AMPAR antagonist is coordinately administered with Carmustine (BCNIJ) to treat an AMPAR positive cancer.
In other coordinate methods and compositions, anti-cancer effective AMPAR
antagonist administration is combined with a secondary anti-cancer agent or therapy, e.g., selected from a transcription inhibitor (e.g._ Terameprocol). a telomere disrupting agent (e.g., 30 TREI inhibitors such as ETP-4707). an inhibitor of a gene splicing protein (e.g., a PRMT5 inhibitor), an indoleamine 2_ 3, dioxegenase (ID()) inhibitor. lapatinib ditosylate enzyme blocker. anti-cancer antibodies. antibody fragments and related -biologics1 for example Adavosertib. tumor treating fields, and radiation. alone or in any combination with other secondary or adjunctive cancer agents and treatments described herein.
bevacizumab.
bortezomib. capecitabine, cetuximab. clofarabine. dasatinib, decitabine, doeetaxel, emend.
erlotinib hydrochloride. exemestane_ fulvestrant. gefitinib. ueincitabine hydrochloride, irnati nib mesylate. imiquimod. lenalidomide. letrozole nelarabine.
oxaliplatin, paclitaxel, 5 docetaxel, paliferm in. panitumumab. pegaspargase_ pemetrexed di sodium, rituximab, sorafenib tosylate, sunitinib malate, tamoxifen citrate, targretin, temozolomide, thalidomide, and/or topotecan hydrochloride. Additional contemplated secondary anti-cancer effective agents in this context include. but are not limited to. interleukin-2.
interferon a. filgrasten_ G-CSF, epoetin alla, erythropoietin. oprelvekin.
trastuzumab, vorinostat. antibiotics, 10 coenzyme q. palladium lipoic complexes including, for example_ poly-MVAK.
antineoplastins, cartilage_ hydrazine sulfate; milk thistle, electrolytes such as calcium carbonate, magnesium carbonate. sodium bicarbonate_ and potassium bicarbonate;
oxidizing agents. including. but not limited to. cesium chloride, potassium chloride, potassium orotate and potassium aspartate: immunoulobulins, colostrum: and vitamin and mineral supplements, 15 including but not limited to. zinc chloride. magnesium chloride, pyridoxine, vitamin B- 12, B
complexes_ folic acid, sodium ascorbate_ and probiotics. Additional secondary therapies may include conventional chemotherapy, radiation therapy. and/or surgery.
In certain illustrative embodiments directed to treatment of glioblastorna (GBM), pancreatic cancer and other AMPAR-dependent types/forms of cancer. the AMP or other 20 AMPAR antagonist is coordinately administered with temozolomide (TMZ).
In related embodiments, the PMP or other AMPAR antagonist is coordinately administered with eisplatin to treat an AMPAR-dependent cancer, for example an AMPAR-positive pancreatic cancer. In other exemplary embodiments. an anti-cancer effective PMP or other AMPAR
antagonist compound is coordinately administered with hydroxyurea to treat an AMPAR
25 positive cancer. In other embodiments. the PMP or other AMPAR antagonist is coordinately administered with Carmustine (BCNIJ) to treat an AMPAR positive cancer.
In other coordinate methods and compositions, anti-cancer effective AMPAR
antagonist administration is combined with a secondary anti-cancer agent or therapy, e.g., selected from a transcription inhibitor (e.g._ Terameprocol). a telomere disrupting agent (e.g., 30 TREI inhibitors such as ETP-4707). an inhibitor of a gene splicing protein (e.g., a PRMT5 inhibitor), an indoleamine 2_ 3, dioxegenase (ID()) inhibitor. lapatinib ditosylate enzyme blocker. anti-cancer antibodies. antibody fragments and related -biologics1 for example Adavosertib. tumor treating fields, and radiation. alone or in any combination with other secondary or adjunctive cancer agents and treatments described herein.
14 In related embodiments. coordinate anti-cancer treatment methods of the invention can include coordinate administration of one or more anti-cancer AMPAR
antagonist compounds, such as PMP_ in combination with one or a plurality of any combination of secondary therapeutic agent(s) or therapy(ies) selected from: NMDA antagonists such as 5 memantine for the treatment of various cancer anti PO- I /MI.- I therapy:
CSF I R inhibitors such as PLX3397 and PLX5622: cannabinoid drugs: anti-rnalarials such as mefloquine.
primaquine, chloroquine, hydroxychloroquine: Riluzole/troriluzole treatment:
antihistamines such as clemastine: biguanides such as metforrnin or phenformin: anti-cancer biologics such as Pembrolizumab or Nivolumab: selective serotonin reuptake inhibitors (SSR1s): tricyclic 10 antidepressants (TCAs): AMPA receptor positive allosteric modulators (Ampakines):
levetiracetam (Keppra). and other agents. therapies and combinations contemplated herein.
Within exemplary embodiments, typical drug doses or combinatorial drug doses (median or average doses among a treated patient class) may include, for example, peramplanel administered at about 12mg/day (exemplary range 5-50 mg/day), Memantine at
antagonist compounds, such as PMP_ in combination with one or a plurality of any combination of secondary therapeutic agent(s) or therapy(ies) selected from: NMDA antagonists such as 5 memantine for the treatment of various cancer anti PO- I /MI.- I therapy:
CSF I R inhibitors such as PLX3397 and PLX5622: cannabinoid drugs: anti-rnalarials such as mefloquine.
primaquine, chloroquine, hydroxychloroquine: Riluzole/troriluzole treatment:
antihistamines such as clemastine: biguanides such as metforrnin or phenformin: anti-cancer biologics such as Pembrolizumab or Nivolumab: selective serotonin reuptake inhibitors (SSR1s): tricyclic 10 antidepressants (TCAs): AMPA receptor positive allosteric modulators (Ampakines):
levetiracetam (Keppra). and other agents. therapies and combinations contemplated herein.
Within exemplary embodiments, typical drug doses or combinatorial drug doses (median or average doses among a treated patient class) may include, for example, peramplanel administered at about 12mg/day (exemplary range 5-50 mg/day), Memantine at
15 about 20 mg/day. (exemplary ranee 5-75 mg/day). R I tin)) e at about 50mg/day (exemplary range 10-100 mg/day). PLX3397 at about 1000 mg/day (exemplary range 300 2500 mg/day).
Anti-malarials at about 250 mg every other day (exemplary range 50-200 mg/day or every other day), Metformin at about 2 g/day (exemplary range 300 mg-4 g/day).
Pembrolizumab at about 2 mg/kg every 3 weeks (exemplary range 0.05-10 mtz/kg every 1-4 weeks), Nivolumab 20 at about 3 me/kg every 2 weeks (exemplary range 1-5 mg/kg, every 1-3 weeks).
Levctiracetain at about 500 mg twice a day. Clemastine lumarate at about 2.5 mg per day.
(exemplary range 1-5 lug per day), Escitalopram at about 20 mg./day (exemplary range 5-75 mg/day). sertraline at about 200 mg/day (exemplary ranee 50-800 mg/day), fluoxetine at about 20 mg/day (exemplary range 5-200 mg/day). Imipramine hydrochloride at about 25-50 25 mg/day (exemplary range 2-400 mg/day), Ampakines at about 900rng/day, with high impact ampakincs at about 100/day (exemplary range 25 me-1.5 g/day): CUD at about 100-mg/day. (exemplary range 20-1000 mg/day.): IIIC at about 5- 1 00 mg/day (exemplary range 1-800 mg/day): Ketamine/hydroxynorketamine at about 5-500mg/day (exemplary range mg/day). Disulfiram at about 50-500 me/dak (exemplary range 20-1500 me/day).
or any 30 combination of the foregoing drugs/doses.
In more detailed aspects of the invention employing coordinate treatment with Ampakines. operable ampakines can be selected from a wide variety of known ampakine compounds. Ampakines. while structurally diverse as a whole, show many shared structural and functional features within classes. Roth between and within known ampakine classes, useful drug candidates operable within the anti-cancer methods and compositions of the invention can be identified, selected and proven effective according to the detailed teachings 5 and guidance herein. Following these teachings, anti-cancer active ampakines can be selected among positive allosterie A MPA receptor modulators from within a variety of known ampakine groups. Among the ampakine classes from which operable ampakine candidates for use within the invention can be selected include ainpakines generally classified as: sulfonamide compounds and derivatives, (bis)stilfonamide compounds and derivatives, N-10 substituted sulfonamide compounds and derivatives: heterocyclic sulfonamide compounds and derivatives: heterocycly1 sulfonamide compounds and derivatives: alkenyl sulfonamide compounds and derivatives; cycloalkenvl sulfonamide compounds and derivatives;
cyclopentyl sulfonamide compounds and derivatives: cycloalkylfluoro sulfonamide compounds and; aeetylenic sulfonamide compounds and derivatives; 2-propane-sulfonamide 15 compounds and derivatives: 2-aminobenzenestilfonamide compounds and derivatives:
benzoyl piperidinc and benzoyl compounds and derivatives: pyrrolidine compounds and derivatives: benzoxazine ring compounds and derivatives: acylbenzoxazine compounds and derivatives: carbonvlbenzoxazine compounds and derivatives; substituted 23-benzodiazepin-4-one compounds and derivatives: amidophosphate: monotluoralkyl compounds and 20 derivatives; substituted quinazoline compounds and derivatives;
quainoxaline compounds and derivatives; 2-ethoxy-4.43-(propane-2-sullonylamino)-thiophen-2-y11-biphenyl-4-carboxylic and derivatives; p3;rrole and pyrazole compounds and derivatives: thiadiazine compounds and derivatives; benzofurazan compounds and derivatives: benzothiazidc compounds and derivatives: substituted 5-oxo-5.6.7.8-tetrahydro-4H-l-benzopyran and benzothiopyran 25 compounds and derivatives; benzoxazepine compounds and derivatives;
among known classes of compounds comprising AMPA receptor modulator compounds prospectively useful within the invention.
According to the teachings and examples presented herein, anti-cancer effective ampakines effective within the invention are selected and characterized from among various 30 structural classes of ampakincs, for example, to demonstrate low impact convulsant risk and therapeutically effective anti-cancer activity. In illustrative embodiments provided herein, ampakines from the known class of benzoftirazan ampakine compounds and derivatives (e.g..
as disclosed in U.S. Pat. Nos. 6.110.935: and 6,313.115: and PCT Int'l Pub.
No.
Anti-malarials at about 250 mg every other day (exemplary range 50-200 mg/day or every other day), Metformin at about 2 g/day (exemplary range 300 mg-4 g/day).
Pembrolizumab at about 2 mg/kg every 3 weeks (exemplary range 0.05-10 mtz/kg every 1-4 weeks), Nivolumab 20 at about 3 me/kg every 2 weeks (exemplary range 1-5 mg/kg, every 1-3 weeks).
Levctiracetain at about 500 mg twice a day. Clemastine lumarate at about 2.5 mg per day.
(exemplary range 1-5 lug per day), Escitalopram at about 20 mg./day (exemplary range 5-75 mg/day). sertraline at about 200 mg/day (exemplary ranee 50-800 mg/day), fluoxetine at about 20 mg/day (exemplary range 5-200 mg/day). Imipramine hydrochloride at about 25-50 25 mg/day (exemplary range 2-400 mg/day), Ampakines at about 900rng/day, with high impact ampakincs at about 100/day (exemplary range 25 me-1.5 g/day): CUD at about 100-mg/day. (exemplary range 20-1000 mg/day.): IIIC at about 5- 1 00 mg/day (exemplary range 1-800 mg/day): Ketamine/hydroxynorketamine at about 5-500mg/day (exemplary range mg/day). Disulfiram at about 50-500 me/dak (exemplary range 20-1500 me/day).
or any 30 combination of the foregoing drugs/doses.
In more detailed aspects of the invention employing coordinate treatment with Ampakines. operable ampakines can be selected from a wide variety of known ampakine compounds. Ampakines. while structurally diverse as a whole, show many shared structural and functional features within classes. Roth between and within known ampakine classes, useful drug candidates operable within the anti-cancer methods and compositions of the invention can be identified, selected and proven effective according to the detailed teachings 5 and guidance herein. Following these teachings, anti-cancer active ampakines can be selected among positive allosterie A MPA receptor modulators from within a variety of known ampakine groups. Among the ampakine classes from which operable ampakine candidates for use within the invention can be selected include ainpakines generally classified as: sulfonamide compounds and derivatives, (bis)stilfonamide compounds and derivatives, N-10 substituted sulfonamide compounds and derivatives: heterocyclic sulfonamide compounds and derivatives: heterocycly1 sulfonamide compounds and derivatives: alkenyl sulfonamide compounds and derivatives; cycloalkenvl sulfonamide compounds and derivatives;
cyclopentyl sulfonamide compounds and derivatives: cycloalkylfluoro sulfonamide compounds and; aeetylenic sulfonamide compounds and derivatives; 2-propane-sulfonamide 15 compounds and derivatives: 2-aminobenzenestilfonamide compounds and derivatives:
benzoyl piperidinc and benzoyl compounds and derivatives: pyrrolidine compounds and derivatives: benzoxazine ring compounds and derivatives: acylbenzoxazine compounds and derivatives: carbonvlbenzoxazine compounds and derivatives; substituted 23-benzodiazepin-4-one compounds and derivatives: amidophosphate: monotluoralkyl compounds and 20 derivatives; substituted quinazoline compounds and derivatives;
quainoxaline compounds and derivatives; 2-ethoxy-4.43-(propane-2-sullonylamino)-thiophen-2-y11-biphenyl-4-carboxylic and derivatives; p3;rrole and pyrazole compounds and derivatives: thiadiazine compounds and derivatives; benzofurazan compounds and derivatives: benzothiazidc compounds and derivatives: substituted 5-oxo-5.6.7.8-tetrahydro-4H-l-benzopyran and benzothiopyran 25 compounds and derivatives; benzoxazepine compounds and derivatives;
among known classes of compounds comprising AMPA receptor modulator compounds prospectively useful within the invention.
According to the teachings and examples presented herein, anti-cancer effective ampakines effective within the invention are selected and characterized from among various 30 structural classes of ampakincs, for example, to demonstrate low impact convulsant risk and therapeutically effective anti-cancer activity. In illustrative embodiments provided herein, ampakines from the known class of benzoftirazan ampakine compounds and derivatives (e.g..
as disclosed in U.S. Pat. Nos. 6.110.935: and 6,313.115: and PCT Int'l Pub.
No.
16 W09835950) were screened and developed to identify operable drug candidates within the compositions and methods of the invention. From these investigations exemplary anti-cancer benzolurazan candidates 1-(benzoliirazan-5-ylcarbony1)-4,4-difluoropiperidine, and 4-(benzofurazan-5-ylearbonyft and 1-(benzolurazan-5-ylcarbonyl)morpholine.
Within 5 additional compositions and methods of the invention, low impact ampakines are selected for combinatorial treatment methods of the invention from another ampakine group known collectively as -di-substituted amide ampakines.- These ampakines were first described by Cortex (now RespireRx). as detailed in USSN 12/451515, US Publication No.
US2010/0120764, and PCT/1JS/2008/00627 (incorporated herein in their entirety.
for all 10 purposes). Exemplary di-substituted amide ampakines for use within the invention include N-Methyl-N-tetrahydro-211-p) ran-4-y1-[2.1.3]-benzoxadiazole-5-carboxamide ("CX1739-), Trans-4-[(2.1.3-benzoxadiazol-5-ylcarbonyl)(methypaininojcyclohexyl glycinate hydrochloride (CX1942 ); and. N-(4-trans-hydroxycyclohex)-1)-N-methy142.1,31-benzoxadiazole-5-carboxamide (CXI763). Within related embodiments of the invention, 15 useful low impact. anti-cancer ampakines are selected and demonstrated to be active according to the teachings herein_ having the exemplary annpakine structure I.
below:
A
20 NA herein:
W is oxygen_ sulfur or C11=01:
X, Y and Z are independently selected from the group consisting of-N. or -CR.
wherein:
R is 1-1, -Br. -0_ -F. -CN. -NO7, -010. -SRI. -NRH, -C1-C6 branched or un-branched 25 alkyl_ which may be un-substituted or substituted, wherein:
R' is H, -C1-C6 branched or tin-branched alkyl which_ may be un-substituted or substituted.
F - 0 or S.
Within 5 additional compositions and methods of the invention, low impact ampakines are selected for combinatorial treatment methods of the invention from another ampakine group known collectively as -di-substituted amide ampakines.- These ampakines were first described by Cortex (now RespireRx). as detailed in USSN 12/451515, US Publication No.
US2010/0120764, and PCT/1JS/2008/00627 (incorporated herein in their entirety.
for all 10 purposes). Exemplary di-substituted amide ampakines for use within the invention include N-Methyl-N-tetrahydro-211-p) ran-4-y1-[2.1.3]-benzoxadiazole-5-carboxamide ("CX1739-), Trans-4-[(2.1.3-benzoxadiazol-5-ylcarbonyl)(methypaininojcyclohexyl glycinate hydrochloride (CX1942 ); and. N-(4-trans-hydroxycyclohex)-1)-N-methy142.1,31-benzoxadiazole-5-carboxamide (CXI763). Within related embodiments of the invention, 15 useful low impact. anti-cancer ampakines are selected and demonstrated to be active according to the teachings herein_ having the exemplary annpakine structure I.
below:
A
20 NA herein:
W is oxygen_ sulfur or C11=01:
X, Y and Z are independently selected from the group consisting of-N. or -CR.
wherein:
R is 1-1, -Br. -0_ -F. -CN. -NO7, -010. -SRI. -NRH, -C1-C6 branched or un-branched 25 alkyl_ which may be un-substituted or substituted, wherein:
R' is H, -C1-C6 branched or tin-branched alkyl which_ may be un-substituted or substituted.
F - 0 or S.
17 A is I-1, or -C1-C6 branched or un-branched alkyl, which may be un-substituted or substituted_ -C2-C6 branched or un-branched alkenyl. which may be un-substituted or substituted, -C2-C6 branched or un-branched alkynyl. which may be un-substituted or substituted, -C3-C7 cycloalkyl which may be tin-substituted or substituted, -5 alkylcycloalkyl which may be un-substituted or substituted, aryl or heterocycle which may be un-substituted or substituted. alkylaryl which may be un-substituted or substituted. alkylheterocycle which may be tin-substituted or substituted n=0. I. 2. 3_ 4. 5. or 6:
is a -C3-C7 cycloalkyl_ which may be un-substituted or substituted, a -C4-C7 10 azacycloalkyl. which may be tin-substituted or substituted, a C7-C10 bicycloalkyi which may be un-substituted or substituted, a -C7-C10 azabicycloalkyl which may be tin-substituted or substituted. aryl which may be un-substituted or substituted or a heterocycle which may be un-substituted or substituted:
13 is -C=. C-R3, 0, N. S. ('-0. S-0 or SO2.
15 Fr is I-1. a halogen (preferabl) 1--). Oft 0-alkyl, cyano. or a -CI-C6 alkyl group which is un-substituted or substituted and which optionally, forms a C3-C.7 cycloalkyl group with D: and D is absent when 13 is 0. S. 5-0, C:J:0 or SO2. or if present. is bonded to B
when 13 is - C. -C-R" or N, and is II. a halogen (preferably F). Rh, a -Ci-C6 branched or un-20 branched alkyl. which may he un-substituted or substituted and which optionally, Forms a (71-C7 cycloalkyl group with Ra. a -C2-C6 branched or un-branched alkenyl, which may be un-substituted or substituted, a -C2-C6 branched or un-branched alkynyl, which may be tin-substituted or substituted. a -C3-C7 cycloalkyl which may be un-substituted or substituted. an aryl which may be tin-substituted or substituted , a 25 heterocycle which may be un-substituted or substituted. a -C2-C7 carboxyalkyl which may be un-substituted or substituted. a carboxyaryl which may be un-substituted or substituted, a earboxyheteroaryl which may be un-substituted or substituted. a -Ci-C7 sulfony lalkyl i.shich may be un-substituted or substituted. a sullony-laryl which may be un-substituted or substituted or a sullonylheteroaryl which may be un-substituted or 30 substituted. or when B is -C-Ra. R" and D optionally form a -N-Re or a =N-OW
group with B. wherein Re is 14 or an unsubstituted or substituted C1-C7 alkyl group, or
is a -C3-C7 cycloalkyl_ which may be un-substituted or substituted, a -C4-C7 10 azacycloalkyl. which may be tin-substituted or substituted, a C7-C10 bicycloalkyi which may be un-substituted or substituted, a -C7-C10 azabicycloalkyl which may be tin-substituted or substituted. aryl which may be un-substituted or substituted or a heterocycle which may be un-substituted or substituted:
13 is -C=. C-R3, 0, N. S. ('-0. S-0 or SO2.
15 Fr is I-1. a halogen (preferabl) 1--). Oft 0-alkyl, cyano. or a -CI-C6 alkyl group which is un-substituted or substituted and which optionally, forms a C3-C.7 cycloalkyl group with D: and D is absent when 13 is 0. S. 5-0, C:J:0 or SO2. or if present. is bonded to B
when 13 is - C. -C-R" or N, and is II. a halogen (preferably F). Rh, a -Ci-C6 branched or un-20 branched alkyl. which may he un-substituted or substituted and which optionally, Forms a (71-C7 cycloalkyl group with Ra. a -C2-C6 branched or un-branched alkenyl, which may be un-substituted or substituted, a -C2-C6 branched or un-branched alkynyl, which may be tin-substituted or substituted. a -C3-C7 cycloalkyl which may be un-substituted or substituted. an aryl which may be tin-substituted or substituted , a 25 heterocycle which may be un-substituted or substituted. a -C2-C7 carboxyalkyl which may be un-substituted or substituted. a carboxyaryl which may be un-substituted or substituted, a earboxyheteroaryl which may be un-substituted or substituted. a -Ci-C7 sulfony lalkyl i.shich may be un-substituted or substituted. a sullony-laryl which may be un-substituted or substituted or a sullonylheteroaryl which may be un-substituted or 30 substituted. or when B is -C-Ra. R" and D optionally form a -N-Re or a =N-OW
group with B. wherein Re is 14 or an unsubstituted or substituted C1-C7 alkyl group, or
18 when B is ¨C-R". R" and D optionally form a ¨14-Re or a ¨N-ORe group with B.
wherein Re is H or an unsubstituted or substituted CI-C7 alkyl group: and Rb is H, a -CI-C7 alkyl group which ma v he branched or un-branched. un-substituted or substituted or a -C2-C7 acvl group which may be un-substituted or substituted.
Other exemplary ampakines useful within the combinatorial methods herein include include compounds according to formula II below:
/N, 10 )n 0\
A
wherein:
A is -C1-C6 branched or un-branched alkyl, which may be un-substituted or substituted. a C3-C7 cycloalkyl which may be un-substituted or substituted;
n is O. I _ 1 or 3:
B is C-R". 0 or C-0:
R" is ELF. -OH or alkyl and D is absent (when B is 0). is H or OH when Ra is H or alkyl, or is F when R is F, or a pharmaceutically acceptable salt. solvate. or polyinorph thereof.
Yet additional exemplary ampakines for use within the invention include compounds according to formula III below:
0\
A
I II
w herein:
A is a C1-C6 alkyl which may be substituted or on-substituted:
B is C-ie. 0 or C-0:
Ra is H. F. -011 or alkyl and D is absent (when B is 0). is 1-1 or OH when R" is II or alkyl. or is F when R" is F. or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
wherein Re is H or an unsubstituted or substituted CI-C7 alkyl group: and Rb is H, a -CI-C7 alkyl group which ma v he branched or un-branched. un-substituted or substituted or a -C2-C7 acvl group which may be un-substituted or substituted.
Other exemplary ampakines useful within the combinatorial methods herein include include compounds according to formula II below:
/N, 10 )n 0\
A
wherein:
A is -C1-C6 branched or un-branched alkyl, which may be un-substituted or substituted. a C3-C7 cycloalkyl which may be un-substituted or substituted;
n is O. I _ 1 or 3:
B is C-R". 0 or C-0:
R" is ELF. -OH or alkyl and D is absent (when B is 0). is H or OH when Ra is H or alkyl, or is F when R is F, or a pharmaceutically acceptable salt. solvate. or polyinorph thereof.
Yet additional exemplary ampakines for use within the invention include compounds according to formula III below:
0\
A
I II
w herein:
A is a C1-C6 alkyl which may be substituted or on-substituted:
B is C-ie. 0 or C-0:
Ra is H. F. -011 or alkyl and D is absent (when B is 0). is 1-1 or OH when R" is II or alkyl. or is F when R" is F. or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
19 Other exemplary ampakines for use within the invention include compounds according to formula IV below:
lb¨. III
IV
wherein:
A is a C1-C6 alkyl which may be substituted or tin-substituted.
n is 0. I or 2. or a pharmaceutically acceptable salt. solvate. or polymorph thereof Other exemplary embodiments include compounds according to formula V
below:
N____4110 A
V
15 wherein:
A is a (21-C6 alkyl which may be substituted or un-substituted.
is It F. or CI-C4 alkyl.
R2 is It F. Cl\i. a heterocycle which may be substituted or un-substituted or OR3.
R3 is H. CI-C6 alkyl which may be substituted or un-substituted, or a
lb¨. III
IV
wherein:
A is a C1-C6 alkyl which may be substituted or tin-substituted.
n is 0. I or 2. or a pharmaceutically acceptable salt. solvate. or polymorph thereof Other exemplary embodiments include compounds according to formula V
below:
N____4110 A
V
15 wherein:
A is a (21-C6 alkyl which may be substituted or un-substituted.
is It F. or CI-C4 alkyl.
R2 is It F. Cl\i. a heterocycle which may be substituted or un-substituted or OR3.
R3 is H. CI-C6 alkyl which may be substituted or un-substituted, or a
20 pharmaceutically acceptable salt, solvate, or polymorph thereof.
Other exemplary ampakines for use within the invention include compounds according to formula VI below:
OH
71, IN
0\
A
V I
5 wherein:
A is a C1-C6 alkyl which may he substituted or tin-substituted.
R. is H. or C i-C4 alkyl, or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
Other exemplary ampakines for use within the invention include compounds 10 according to formula VII below:
0 Cr-D
/
Me VII
wherein:
B is C-R", 0 or C=0:
15 R" is 11, F. -OH or alkyl and D is absent (when B is 0). is 11 or 011 when 113 is 11 or alkyl, or is F when Rd is F. or a pharmaceutically acceptable salt_ solvate_ or poly morph thereof Other exemplary ampakines for use within the invention include compounds according to formula VIII below:
CreD
20 Me VIII
µ herein:
B is C-R". 0 or CO:
R" is H. F. -01-1 or alkyl and
Other exemplary ampakines for use within the invention include compounds according to formula VI below:
OH
71, IN
0\
A
V I
5 wherein:
A is a C1-C6 alkyl which may he substituted or tin-substituted.
R. is H. or C i-C4 alkyl, or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
Other exemplary ampakines for use within the invention include compounds 10 according to formula VII below:
0 Cr-D
/
Me VII
wherein:
B is C-R", 0 or C=0:
15 R" is 11, F. -OH or alkyl and D is absent (when B is 0). is 11 or 011 when 113 is 11 or alkyl, or is F when Rd is F. or a pharmaceutically acceptable salt_ solvate_ or poly morph thereof Other exemplary ampakines for use within the invention include compounds according to formula VIII below:
CreD
20 Me VIII
µ herein:
B is C-R". 0 or CO:
R" is H. F. -01-1 or alkyl and
21 D is absent (when B is 0). is H or Oil when R" is 11 or alkyl. or is F when Ra is F. or a pharmaceutically acceptable salt, solvate. or polyrnorph thereof.
Other exemplary ampakincs for use within the invention include compounds according to formula IX below:
0 )JR4 N
/
A
IX
wherein:
A is a C1-C6 alkyl which may be substituted or un-substituted, RI is H. or CI-Cr alkyl.
R2 is H. or a C1-C6 alkyl which may be substituted or un-substituted.
R3 is II. or a C -Co alkyl which may he substituted or un-substituted.
R4 is II. or a C1-C6 alkyl which may be substituted or un-substituted, or a pharmaceutically acceptable salt, solvate or polymorph thereof.
In more detailed embodiments, anti-cancer active compounds are selected from compounds of Formulas I -IX above that are already isolated and characterized, selected from: Al-Cycloheptyl-N-methy1[2.1,31-benzoxadiazole-5-carboxamide:
Dimethylcyclohexyl-N-methy142. I .31-benzoxadiazole-5-carboxamide: N-Methyl-N-spirol_2.51oct-6-y142. l.3]-benzoxadiazole-5-carboxamide: N-Cyc lohexyl-N-methy1-[2.1.3]-benzoxadiazole-5-carboxamide: N-Cyclopentyl-N-methyl-[2,1,3 I-benzoxad iazo le-carboxamide: N-Cyclobutyl-N-methyl-I2.1.31-benzoxadiazole-5-carboxamide: N-C)clohexy1-12.1.3.1-benzoxadiazole-5-carboxarnide: N-Cyclopenty1-1-2.1.31-benzoxadiazole-carboxamide: N-Cyclobtity1-12, I .31-benzoxadiazole-5-carboxamide: N-(c is-4-Cyanocy c lohexyl)-N-rinethyl-[2. I .3 I-be nzoxadiazole-5-carboxam ide: N-(lrans-4-CyanocyclohexyI)-N-methyl-[2.1,3I-benzoxadiazolc-5-carboxam ide: N-Methyl-N-tetrahydro-211-pyran-4-y1-12.1.31-benzoxadiazole-5-carboxamide (CXI739): N-D3-Methyl-N4etrahydro-2H-pyran-4-y112. I .31-benzoxadiazole-5-carboxamide: N-(Tetrahydro-2H-pyran-4-y1)-12,1.3-1-benzoxadiazole-5-carboxamide: N-(Tetrahydro-211-pyran-3-y1)12,1.3]-benzoxadiazole-5-carboxamide: N-Methyl-N-(tetrahydro-21/-pyran-3-y1)42,1.31-berizoxacliazole-5-carboxamide: .11-Fthyl-N-tetrahydro-2H-pyran-4-y142.131-
Other exemplary ampakincs for use within the invention include compounds according to formula IX below:
0 )JR4 N
/
A
IX
wherein:
A is a C1-C6 alkyl which may be substituted or un-substituted, RI is H. or CI-Cr alkyl.
R2 is H. or a C1-C6 alkyl which may be substituted or un-substituted.
R3 is II. or a C -Co alkyl which may he substituted or un-substituted.
R4 is II. or a C1-C6 alkyl which may be substituted or un-substituted, or a pharmaceutically acceptable salt, solvate or polymorph thereof.
In more detailed embodiments, anti-cancer active compounds are selected from compounds of Formulas I -IX above that are already isolated and characterized, selected from: Al-Cycloheptyl-N-methy1[2.1,31-benzoxadiazole-5-carboxamide:
Dimethylcyclohexyl-N-methy142. I .31-benzoxadiazole-5-carboxamide: N-Methyl-N-spirol_2.51oct-6-y142. l.3]-benzoxadiazole-5-carboxamide: N-Cyc lohexyl-N-methy1-[2.1.3]-benzoxadiazole-5-carboxamide: N-Cyclopentyl-N-methyl-[2,1,3 I-benzoxad iazo le-carboxamide: N-Cyclobutyl-N-methyl-I2.1.31-benzoxadiazole-5-carboxamide: N-C)clohexy1-12.1.3.1-benzoxadiazole-5-carboxarnide: N-Cyclopenty1-1-2.1.31-benzoxadiazole-carboxamide: N-Cyclobtity1-12, I .31-benzoxadiazole-5-carboxamide: N-(c is-4-Cyanocy c lohexyl)-N-rinethyl-[2. I .3 I-be nzoxadiazole-5-carboxam ide: N-(lrans-4-CyanocyclohexyI)-N-methyl-[2.1,3I-benzoxadiazolc-5-carboxam ide: N-Methyl-N-tetrahydro-211-pyran-4-y1-12.1.31-benzoxadiazole-5-carboxamide (CXI739): N-D3-Methyl-N4etrahydro-2H-pyran-4-y112. I .31-benzoxadiazole-5-carboxamide: N-(Tetrahydro-2H-pyran-4-y1)-12,1.3-1-benzoxadiazole-5-carboxamide: N-(Tetrahydro-211-pyran-3-y1)12,1.3]-benzoxadiazole-5-carboxamide: N-Methyl-N-(tetrahydro-21/-pyran-3-y1)42,1.31-berizoxacliazole-5-carboxamide: .11-Fthyl-N-tetrahydro-2H-pyran-4-y142.131-
22 be nzoxad azo le-5-ca rboxami de: N-Cy-clohexyl-N-ethy142.1,3J-benzoxadiazole-carboxam ide:N-(Cyc lohexylmethyl)-N-methy142.1.31-benzoxadiazole-5-carboxamide; N-Benzy1-N-methyl-[2,1,311-benzoxad iazolc-5-carboxamide: N-Methy 1-N-(tetrahydroluran-2-ylmethy1)12.1,31-benzoxadiazole-5-carboxamide: N-M ethy 1-N-pyrid n-3-y142.1,3]-5 benzoxad iazo le-5-earboxami de: N-Methyl-N-pheny1-12,1,31-benzoxadiazole-5-carboxamide N-Cyclopropyl-N-tetrahydro-211-pyran-4-y142,1,31-benzoxadiazole-5-earboxamide N-Tetrahydro-2H-pyran-4-yl-N-(2.2.2-trif1uoroethy1)42.1.31-benzoxadiazole-5-carboxarnide:
tert-Buty1-44([2_ I .31-benzoxadiazol-5-ylearbonyl)(methyl)amino]pipericline-1-carboxylate:
N-Methyl-N-piperidin-4-y1-12.1.31-ben7oxadiazole-5-carboxam ide hydrochloride:
N-Methyl-10 N-(1-rnethylpiperidin-4-y1)-[2.1.31-benzoxadiazole-5-carboxam ide: N-(1-Acetylpiperid i n-4-y1)-N-methy112,1.3]-benzoxad azole-5-carboxam ide: N-( -Formylpiperidin-4-y1)-N-methyl-[2,1.311-benzoxadiazole-5-carboxamide: N-Methyl-N-I 1-( methylsulfonyl]
piperidin-4-y1)-[2.1.3 I-benzoxadiazole-5-carboxamide: N-Methy 1-N-(tetrahydro-21-1-pyran-4-y1)42,13]-benzothiadiazole-5-carboxam ide: N'-Meth?..:1-N-(tetrahyd ro-211-thiopy ran-4-y1)42,1.31-15 benzoxadiazole-5-earboxamide: N-Methyl-N-(1-oxidotetrahydro-2H-thiopyran-4-y1)-[2.1,31-benzoxadiazole-5-earboxamide: N-Methyl-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-5/1)-[2,1.31-benzoxadiazole-5-carboxamide: N-Methyl-N-tetrahydro-2H-pyran-4-ylquinoxaline-6-carboxam ide: N-Methyl-N-(4-oxocyclohexy1)[2.1.31-benzoxadiazole-5-carboxam ide; N44-(Hyd roxy im ino)cyclohexyll-N-rnethyl-I 2.1.3[-benzoxadiazole-5-carboxamide:
N
20 (Methoxyimino)eyelohexy1J-N-rnethy112.1.31-benzoxadiazole-5-carboxamide;
N-(4,4-Dill uoroeyc lohexyl)-N-methy142. I .31-benzoxad iazole-5-carboxam ide: N-(4-fluoroc ye lohex-3-en-l-y1)-N-methy142.1.31-bentoxad iazol e-5-ca rboxam idc: N-(4-trans-H)droxycyclohexy1)42. I _31-benzoxacliazole-5-carboxam ide: N-(irans-4-1-1ydroxy-4-methylcyclohexy1)-12.1.3J-bentoxadiazole-5-carboxamide: N-(cis-4-11vdroxy-4-25 methylcyclohexyl)-N-methyl-[2.1.3]-benzoxadiazole-5-carboxam ide: N-(trctus-4-1 lydroxy-4-methyleye lohexyl)-N-m ethy142.1.3]-benzoxadiazolc-5-carboxam ide: N-(cis-4-Hydroxy-4-ethylcyc1ohexyl)-N-methy1-12.1.31-benzoxadiazole-5-carboxam ide: N-(irans--4-Hydroxv-4-ethylcyclohexy.1)-N-meth y112.1_3 [-benzoxad iazo le-5-carboxam ide: N-(cis-4-Ethyny1-4-hydroxy eye lohexyl )-N-methyl-I 2.1.31-benzoxadiazole-5-carboxamide: N-(eis-4-But-3-en-1-30 y1-4-hytlroxycyclohexyl)-N-methy1[2.1.31-benzoxadiazole-5-carboxam ide:
N-(trarts-4-But-3-en-l-y1-4-hvdroxycyc lohexyl )-N-methy142.1.3]-benzoxad iazole-5-carboxa m ide: N-(4-trans--1-lyd roxycyc lohexyl)-N-methy142_1_3]-benzoxad iazole-5-earboxam ide (CX1763): N-(4-1rans-1-1ydroxycyc1ohexy1)-N-1)3-rnethy142.1.3 I-benzoxadiazole-5-carboxamide: N-(irans-4-Metho\vevelohexyl)-AlmetIn142_131-bentoxadiazole-5-carboxamide:
tert-Buty1-44([2_ I .31-benzoxadiazol-5-ylearbonyl)(methyl)amino]pipericline-1-carboxylate:
N-Methyl-N-piperidin-4-y1-12.1.31-ben7oxadiazole-5-carboxam ide hydrochloride:
N-Methyl-10 N-(1-rnethylpiperidin-4-y1)-[2.1.31-benzoxadiazole-5-carboxam ide: N-(1-Acetylpiperid i n-4-y1)-N-methy112,1.3]-benzoxad azole-5-carboxam ide: N-( -Formylpiperidin-4-y1)-N-methyl-[2,1.311-benzoxadiazole-5-carboxamide: N-Methyl-N-I 1-( methylsulfonyl]
piperidin-4-y1)-[2.1.3 I-benzoxadiazole-5-carboxamide: N-Methy 1-N-(tetrahydro-21-1-pyran-4-y1)42,13]-benzothiadiazole-5-carboxam ide: N'-Meth?..:1-N-(tetrahyd ro-211-thiopy ran-4-y1)42,1.31-15 benzoxadiazole-5-earboxamide: N-Methyl-N-(1-oxidotetrahydro-2H-thiopyran-4-y1)-[2.1,31-benzoxadiazole-5-earboxamide: N-Methyl-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-5/1)-[2,1.31-benzoxadiazole-5-carboxamide: N-Methyl-N-tetrahydro-2H-pyran-4-ylquinoxaline-6-carboxam ide: N-Methyl-N-(4-oxocyclohexy1)[2.1.31-benzoxadiazole-5-carboxam ide; N44-(Hyd roxy im ino)cyclohexyll-N-rnethyl-I 2.1.3[-benzoxadiazole-5-carboxamide:
N
20 (Methoxyimino)eyelohexy1J-N-rnethy112.1.31-benzoxadiazole-5-carboxamide;
N-(4,4-Dill uoroeyc lohexyl)-N-methy142. I .31-benzoxad iazole-5-carboxam ide: N-(4-fluoroc ye lohex-3-en-l-y1)-N-methy142.1.31-bentoxad iazol e-5-ca rboxam idc: N-(4-trans-H)droxycyclohexy1)42. I _31-benzoxacliazole-5-carboxam ide: N-(irans-4-1-1ydroxy-4-methylcyclohexy1)-12.1.3J-bentoxadiazole-5-carboxamide: N-(cis-4-11vdroxy-4-25 methylcyclohexyl)-N-methyl-[2.1.3]-benzoxadiazole-5-carboxam ide: N-(trctus-4-1 lydroxy-4-methyleye lohexyl)-N-m ethy142.1.3]-benzoxadiazolc-5-carboxam ide: N-(cis-4-Hydroxy-4-ethylcyc1ohexyl)-N-methy1-12.1.31-benzoxadiazole-5-carboxam ide: N-(irans--4-Hydroxv-4-ethylcyclohexy.1)-N-meth y112.1_3 [-benzoxad iazo le-5-carboxam ide: N-(cis-4-Ethyny1-4-hydroxy eye lohexyl )-N-methyl-I 2.1.31-benzoxadiazole-5-carboxamide: N-(eis-4-But-3-en-1-30 y1-4-hytlroxycyclohexyl)-N-methy1[2.1.31-benzoxadiazole-5-carboxam ide:
N-(trarts-4-But-3-en-l-y1-4-hvdroxycyc lohexyl )-N-methy142.1.3]-benzoxad iazole-5-carboxa m ide: N-(4-trans--1-lyd roxycyc lohexyl)-N-methy142_1_3]-benzoxad iazole-5-earboxam ide (CX1763): N-(4-1rans-1-1ydroxycyc1ohexy1)-N-1)3-rnethy142.1.3 I-benzoxadiazole-5-carboxamide: N-(irans-4-Metho\vevelohexyl)-AlmetIn142_131-bentoxadiazole-5-carboxamide:
23 Methoxycyclohexyl)-N-methy1[2A131-benzoxadiazole-5-carbothioamide; N-(4-cis-Hydroxycyclohexyl)-N-methyl-12,1.3 I-benzoxadiazole-5-carboxamide; N-Methyl-N-ftran.s--4-(211-tetrazol-2-y0cyclohexy1112,1,31-benzoxadiazole-5-carboxarnide: N-(irans-4-Azidocycbahexyl)-N-Inethyl-[2..1,3]-benzoxadiazole-5-carboxamide: N'-(trans-4-5 Aminocyclohexyl)-N-methy1-12.1.31-benzoxadiazole-5-carboxamide; N-(cis-3-Hydroxycyclohexy1)-N-methyl-I2.1.31-benzoxad iazole-5-carboxamide: N-(irans-3-Hydroxycyclohexyl)-N-met1iy112,1,3 J-benzoxadiazole-5-carboxamide: N-M et hyl-N-(3-oxocyclohexy1)12.1.31-benzoxadiazole-5-carboxam ide: N-Methyl-N-(3.3-d i Iluorocyc lohexyl )-[2.1.31-benzoxad iazole-5-carboxamide: N--(2-H yd roxycye lohexyl)-N-10 methyl-42.1.3 J-benzoxadiazole-5-carboxam ide: N-Methyl-N-(2-oxocyclohexy1)42.1,31-benzoxadiazolc-5-carboxamide: N-Methyl-N-(2,2-difluorocyclohexyl)-12,1,3)-benzoxadiazole-5-carboxamide; N-(2-Hydroxytetrahydro-2H-pyran-4-y1)42.1.31-benzoxadiazole-5-carboxamide: N-(2-oxotetrahydro-2H-pyran-4-y1)12,1,3]-benzoxadiazole-5-carboxamide: N-Methyl-N-(2-oxotetrahydro-2H-pyran-4-)=1)-[2. I ,31-benzoxadiazole-5-15 carboxamide; N-(2-Hyd roxytetrahydro-2 H-pyran-4-y1)-N-methy142, 1.3]-benzoxad iazo carboxamide; trans-4-[(2.1.3-Benzoxadiazo1-5-ylcarbonyl)(methyl)amino]cyclohexyl N,N-dimethyl glycinate hydrochloride: tratts-4-[(2.1.3-Benzoxadiazol-5-ylcarbonyl)(methyl)amino]cyclohexyl L-alaninate hydrochloride: N- (R)-Tetrahydrofuran-3-y1-12.1.3-1-benzoxad iazole-5-earboxam ide; N-M ethy 1-N-(R)-tetrahydrofuran-3-y142,1,3]-20 benzoxadiazole-5-carboxamide: treurs-4-[(2.13-Benzoxadiazol-5-ylcarbonyliOnethyDaminolcyclohcxyl glycinate hydrochloride; N-2-(4-Morpholinyl)ethyl-[2,1.31-benzoxad iazole-5-carboxam ide: N-Methy1-N-2-(4-morpholiny pethy142,1,31-benzoxadiazole-5-carboxamide hydrochloride; N-Methyl-N-tetrahydro-2H-pyran-4-y1-1.2,1.3]-benzoxacliazole-5-carbothioamide (CX 1739): 1rans-41(2,1,3-Benzoxad iazol-5-25 ylcarbonyl)(methyparninolcyclohexyl L-valinate hydrochloride: irans-4-[(2,1.3-Benzoxadiazo1-5-ylcarbonyl)(methyl)aminol-1-methylcyclohexylN.N-dimethyl glycinate hydrochloride: N-Methy1-N-tetrahydro-2thpyran-4-ylrnethy142.1.31-benzoxadiazole-5-carboxani ide: and trans-4-[(2. 1.3-13enzoxad iazo I-5-y learbony I
)(methyl)amino1-1-methylcyclohexyl glycinate hydrochloride (C X1942 ).
30 Within additional compositions and methods of the invention, low impact ampak Ines are emploNed in the methods and compositions of the invention, selected from yet additional ampakine groups. including -"bicyclic amide ampakines.- Among the many.
bicyclic amide ampakines candidates for use within the invention are the following exemplary species: 8-Azabicyclo[3.2.1]oct-8-y1([2.1.31-benzoxadiazol-5-y1)methanone:
)(methyl)amino1-1-methylcyclohexyl glycinate hydrochloride (C X1942 ).
30 Within additional compositions and methods of the invention, low impact ampak Ines are emploNed in the methods and compositions of the invention, selected from yet additional ampakine groups. including -"bicyclic amide ampakines.- Among the many.
bicyclic amide ampakines candidates for use within the invention are the following exemplary species: 8-Azabicyclo[3.2.1]oct-8-y1([2.1.31-benzoxadiazol-5-y1)methanone:
24 ([2,1,3]-13enzoxadiazol-5-ylcarbony1)-8-azabicyclo[3.2.1 loctan-3-one: t2, I
.3]-Benzoxadiazol-5-y1(3.3-difluoro-8-azabicyclo[3.2.1joct-8-yl)methanone:
ench12,1,3]-Benzoxadiazol-5-y1(3-hydroxy-8-atabicyclo[3.2.1loct-8-y1)inethanone; aro-12.13k Bertioxadiazol-5-y,r1(3-hydroxy-8-azabicyclol 3.2.1 loct-8-yflinethanone; 2-Azabicy-clol 2.2.1 11iept-2-y1(12.13-benzoxadiazol-5-y1)methanone: 1-Azabicyclo[2.2.11hept-1-y1(12,1.31-benzoxadiazo I-5-y Dinethanone: 2-Azabicyclo12.2.2]oct-2-y1([2, I
.31-benzoxadiazol-5-yl)methanone: 12. I .3]-13enzoxadiazol-5-v1(5.6-dichloro-2-azabicyclo[2.2.11hept-2-yl)nriethanone. Additional bicyclic amide ampakines for prospective use within the anti-cancer methods and compositions of the invention include, but are not limited to. the following exemplary species: [2.1.31-13enzoxadiazol-5-y1(3-11uoro-8-azabicyclo[3.2.1]oct-2-en-8-y1)methanone: 2 -Az_abicyc lo12.2.11hept-5-en-2-y1([2.1,3]-benzoxadiazol-5-yl)methanone: R-2-Azabicyclo[2.2.11hept-5-en-2-v1([2.1.31-benzoxadiazol-5-yl)methanone: S-2-Azabicyclo[2.2.11hept-5-en-2-y1(12. I 31-benzoxadiazol-5-yl)methanone; and [2.1.3]-13enzoxadiazo1-5-y1(2-oxa-5azab1cyc10[2.2.11hept-5-yl)rnethanone.
Yet additional ampakinc compounds for use within the invention will be selected according to the teachings herein_ using known AMPA receptor modulator compounds, reagents, preparative methods and other tools as disclosed in the following publications, each of which is incorporated herein for all purposes: PCT Intl Pub. No. WO
94/02475 and related U.S. Pat. Nos. 5.773.434. 5,488,049, 5,650.409, 5,736,543, 5347.492.
5,773.434, 5,891_876. 6,030,968. 6.274,600, 6.329.368. 6.941159_ and 7.026,475; U.S. Pat.
Pub. No. 20020055508: U.S. Pat. Nos. 6.174.921 6301816. 6358.981, 6.362,230, 6.500.865_ 6,515,026. and 6.552.086: PCI Intl Pub. Nos. WO 0190057. WO
0190056, WO
0168592. WO 0196289. WO 02098846. WO 0006157. WO 9833496_ WO 0006083. WO
0006148. WO 0006149. WO 9943285. and WO 9833496: W00194306: U.S. Pat. No.
6,525.099 and PCT Int'l Pub. No. WO 0006537: U.S. Pat. No. 6.355..655 and PCT
Intl Pub.
Nos. W00214294. W00214275. and W00006159: U.S. Pat. No. 6.358,982 and PCT
Pub. No. W00006158: U.S. Pat. No. 6.387.954 and PCI Int'l Pub. No. W00006539;
PCT
Intl Pub. No. W002098847: U.S. Pat. No. 6.639.107 and PCI Intl Pub. No.
W00142203;
PCT Intl Pub. No. W00232858: PCT Int'l Pub. No. W00218329; U.S. Pat. No.
6.596_716 and PCT Intl Pub. Nos: W02006087169. W02006015827. W02006015828., W02006015829. W02007090840. and W02007090841: W002089734: U.S. Pat. Nos.
5.650.409_ 5.747.492. 5.783.587. 5_852.008. and 6.274.600: U.S. Pat. Nos.
5,736.543, 5,962.447. 5.985.871. and PCT Intl Pub. Nos. WO 9736907 and W09933469: U.S.
Pat. No.
6,124.278. and PCT Int'l Pub. No. W09951240: PCT Int'l Pub. No. W003045315;
U.S. Pat.
No. 5_891.871: U.S. Pat. Nos. 6.1 10_935 and 6.313.115. and Pcr Int'l Pub. No.
W09835950;
PCT Int'l Pub. No. W09812185: PCT Intl Pub. No. W00075123: U.S. Pat. No.
6,521,605 and PCT Intl Pub. No. W00006176: PCT 1nel Pub, No. WO 0066546; PCT Intl Pub.
No.
WO 9944612; PCT Int'l Pub. No. W02007060144; U.S. Pat. Pub. No. 20060276532;
U.S.
Pat. Pub. No. 20070066573: U.S. Pat. Pub. No. 20070004709: U.S. Pat. Pub. No.
20040171605: PCT Intl Pub. Nos. WO 9942456_ WO 0006156, and WO 0157045_ and U.S.
Pat. No. 6,617_351.
Additional description and background pertaining also to specific positive allosteric AMPA receptor modulators, their preparation_ use and selection within the compositions and methods of the invention_ is provided in the following references, incorporated herein in toto for all purposes: For bervolurazan compounds-PCI
patent application PCT/US98/02713. United States patent application Serial No.
08/800,108. now United States Patent 6.110,935. United States patent application Serial No.
09/355,139, now United States Patent 6,313,115, United States patent application. Serial No.
09/834,349;
United States patent application, Serial No. 09/845_128. now United States Patent 6,730,677;
For di-substituted amide ampakines-PCT patent application PCT/US2008/00627 I, United States patent application Serial No. 12/451_5 15. now United States Patent 8,013,003. United States patent application. Serial No. 13/226.146_ now issued United States Patent 8.404482, and United States patent application_ Serial No. 13/755_210. now issued United States Patent 8.642.633; For bicyclic amide aunpakines-PCT patent application PCT/U52008/009508, United States Provisional patent application. Serial No. 60/964_362: United States patent application, Serial No. 12/657.908_ now United States Patent 8_ [19.631 United States patent application. Serial No. 12/733.073. now United States Patent 8,263,591. United States patent application. Serial No. 13/348,171. now United States Patent 8.507.482. United States patent application. Serial No. 13/557.681. United States patent application. Serial No. 12/657,924.
now United States Patent 8.168.632, PCT patent application PCT/US2010/000255, and United States Provisional patent application, Serial No. 61/206.642: For bicyclic amide ampakines-PCT patent application PCT/US2010/000254. and United States Provisional patent application. Serial No. 61/206_642: For 3-Substituted-I 1,2.3-113enzotriazinone ampakines-PCT Patent application PCl/US2007/026415. United States Provisional patent application, Serial No. 60/878.626_ United States patent application. Serial No. 12/448_770, PCT patent application PCT/US2007/026416_ United States Provisional application. Serial No. 60/878_503_ United States Provisional patent application_ Serial No.
60/921,433. and United States patent application. Serial No. 12,448.784, now United States Patent 8,173,644:
For 3-substituted 1.2,3-triazin-4-one and 3-substituted 1.3-pyrimidinone ampakines-PCT
patent application PCT/US2008/010877. United States Provisional patent application. Serial No.60/994,548. and United States patent application. Serial No. 12/733,822;
For benzoxazine 5 ampakines-PCT patent application PC1/U598/27027, and United States patent application, Serial No. 08/998.300. now United States Patent 5.985.871: for Acylbenzoxatines ampakines- PCT patent application. Serial No. PCT/US99/07325. and United States patent application 09/054.916, now United States Patent 6.124.278: for Benzoyl Piperidinc/Pyrrolidinc ampakines PCI patent application PCT/US96/07607, and United 10 States patent application Serial No. 08/458367. Filed 2 June 1995. now United States Patent 5,650.409: For betrzoxazine ampakines-PCT patent application. Serial No, PCT/US97/05184, United States patent application. Serial No. 08/624,335. now United States Patent 5,736,543, PCT patent application PCT/US93/06916. and United States patent application, Serial No.
07/919.512. now United States Patent 5_961447; and for carbonylbenzoxazine ampakines-15 PCT patent application PCT/U502/37646. United States Provisional patent application. Serial No. 60/333334. and United States patent application Serial No. 10/495.049. now United States Patent 7,799,913. Each of the foregoing classes and distinct structural groups of ampakine compounds disclosed in the above references are suitable for evaluation to determine operability within the methods and compositions of the invention.
Persons of 20 ordinary skill in the art will recognize that these various compound groups, while being structurally diverse, share common functional characteristics of positive allosteric AMPA
receptor modulation, as described here, and that because of these common functional characteristics, the compounds can be evaluated and determined for their operability according to the inventive discoveries and teachings herein. According to the Examples and
.3]-Benzoxadiazol-5-y1(3.3-difluoro-8-azabicyclo[3.2.1joct-8-yl)methanone:
ench12,1,3]-Benzoxadiazol-5-y1(3-hydroxy-8-atabicyclo[3.2.1loct-8-y1)inethanone; aro-12.13k Bertioxadiazol-5-y,r1(3-hydroxy-8-azabicyclol 3.2.1 loct-8-yflinethanone; 2-Azabicy-clol 2.2.1 11iept-2-y1(12.13-benzoxadiazol-5-y1)methanone: 1-Azabicyclo[2.2.11hept-1-y1(12,1.31-benzoxadiazo I-5-y Dinethanone: 2-Azabicyclo12.2.2]oct-2-y1([2, I
.31-benzoxadiazol-5-yl)methanone: 12. I .3]-13enzoxadiazol-5-v1(5.6-dichloro-2-azabicyclo[2.2.11hept-2-yl)nriethanone. Additional bicyclic amide ampakines for prospective use within the anti-cancer methods and compositions of the invention include, but are not limited to. the following exemplary species: [2.1.31-13enzoxadiazol-5-y1(3-11uoro-8-azabicyclo[3.2.1]oct-2-en-8-y1)methanone: 2 -Az_abicyc lo12.2.11hept-5-en-2-y1([2.1,3]-benzoxadiazol-5-yl)methanone: R-2-Azabicyclo[2.2.11hept-5-en-2-v1([2.1.31-benzoxadiazol-5-yl)methanone: S-2-Azabicyclo[2.2.11hept-5-en-2-y1(12. I 31-benzoxadiazol-5-yl)methanone; and [2.1.3]-13enzoxadiazo1-5-y1(2-oxa-5azab1cyc10[2.2.11hept-5-yl)rnethanone.
Yet additional ampakinc compounds for use within the invention will be selected according to the teachings herein_ using known AMPA receptor modulator compounds, reagents, preparative methods and other tools as disclosed in the following publications, each of which is incorporated herein for all purposes: PCT Intl Pub. No. WO
94/02475 and related U.S. Pat. Nos. 5.773.434. 5,488,049, 5,650.409, 5,736,543, 5347.492.
5,773.434, 5,891_876. 6,030,968. 6.274,600, 6.329.368. 6.941159_ and 7.026,475; U.S. Pat.
Pub. No. 20020055508: U.S. Pat. Nos. 6.174.921 6301816. 6358.981, 6.362,230, 6.500.865_ 6,515,026. and 6.552.086: PCI Intl Pub. Nos. WO 0190057. WO
0190056, WO
0168592. WO 0196289. WO 02098846. WO 0006157. WO 9833496_ WO 0006083. WO
0006148. WO 0006149. WO 9943285. and WO 9833496: W00194306: U.S. Pat. No.
6,525.099 and PCT Int'l Pub. No. WO 0006537: U.S. Pat. No. 6.355..655 and PCT
Intl Pub.
Nos. W00214294. W00214275. and W00006159: U.S. Pat. No. 6.358,982 and PCT
Pub. No. W00006158: U.S. Pat. No. 6.387.954 and PCI Int'l Pub. No. W00006539;
PCT
Intl Pub. No. W002098847: U.S. Pat. No. 6.639.107 and PCI Intl Pub. No.
W00142203;
PCT Intl Pub. No. W00232858: PCT Int'l Pub. No. W00218329; U.S. Pat. No.
6.596_716 and PCT Intl Pub. Nos: W02006087169. W02006015827. W02006015828., W02006015829. W02007090840. and W02007090841: W002089734: U.S. Pat. Nos.
5.650.409_ 5.747.492. 5.783.587. 5_852.008. and 6.274.600: U.S. Pat. Nos.
5,736.543, 5,962.447. 5.985.871. and PCT Intl Pub. Nos. WO 9736907 and W09933469: U.S.
Pat. No.
6,124.278. and PCT Int'l Pub. No. W09951240: PCT Int'l Pub. No. W003045315;
U.S. Pat.
No. 5_891.871: U.S. Pat. Nos. 6.1 10_935 and 6.313.115. and Pcr Int'l Pub. No.
W09835950;
PCT Int'l Pub. No. W09812185: PCT Intl Pub. No. W00075123: U.S. Pat. No.
6,521,605 and PCT Intl Pub. No. W00006176: PCT 1nel Pub, No. WO 0066546; PCT Intl Pub.
No.
WO 9944612; PCT Int'l Pub. No. W02007060144; U.S. Pat. Pub. No. 20060276532;
U.S.
Pat. Pub. No. 20070066573: U.S. Pat. Pub. No. 20070004709: U.S. Pat. Pub. No.
20040171605: PCT Intl Pub. Nos. WO 9942456_ WO 0006156, and WO 0157045_ and U.S.
Pat. No. 6,617_351.
Additional description and background pertaining also to specific positive allosteric AMPA receptor modulators, their preparation_ use and selection within the compositions and methods of the invention_ is provided in the following references, incorporated herein in toto for all purposes: For bervolurazan compounds-PCI
patent application PCT/US98/02713. United States patent application Serial No.
08/800,108. now United States Patent 6.110,935. United States patent application Serial No.
09/355,139, now United States Patent 6,313,115, United States patent application. Serial No.
09/834,349;
United States patent application, Serial No. 09/845_128. now United States Patent 6,730,677;
For di-substituted amide ampakines-PCT patent application PCT/US2008/00627 I, United States patent application Serial No. 12/451_5 15. now United States Patent 8,013,003. United States patent application. Serial No. 13/226.146_ now issued United States Patent 8.404482, and United States patent application_ Serial No. 13/755_210. now issued United States Patent 8.642.633; For bicyclic amide aunpakines-PCT patent application PCT/U52008/009508, United States Provisional patent application. Serial No. 60/964_362: United States patent application, Serial No. 12/657.908_ now United States Patent 8_ [19.631 United States patent application. Serial No. 12/733.073. now United States Patent 8,263,591. United States patent application. Serial No. 13/348,171. now United States Patent 8.507.482. United States patent application. Serial No. 13/557.681. United States patent application. Serial No. 12/657,924.
now United States Patent 8.168.632, PCT patent application PCT/US2010/000255, and United States Provisional patent application, Serial No. 61/206.642: For bicyclic amide ampakines-PCT patent application PCT/US2010/000254. and United States Provisional patent application. Serial No. 61/206_642: For 3-Substituted-I 1,2.3-113enzotriazinone ampakines-PCT Patent application PCl/US2007/026415. United States Provisional patent application, Serial No. 60/878.626_ United States patent application. Serial No. 12/448_770, PCT patent application PCT/US2007/026416_ United States Provisional application. Serial No. 60/878_503_ United States Provisional patent application_ Serial No.
60/921,433. and United States patent application. Serial No. 12,448.784, now United States Patent 8,173,644:
For 3-substituted 1.2,3-triazin-4-one and 3-substituted 1.3-pyrimidinone ampakines-PCT
patent application PCT/US2008/010877. United States Provisional patent application. Serial No.60/994,548. and United States patent application. Serial No. 12/733,822;
For benzoxazine 5 ampakines-PCT patent application PC1/U598/27027, and United States patent application, Serial No. 08/998.300. now United States Patent 5.985.871: for Acylbenzoxatines ampakines- PCT patent application. Serial No. PCT/US99/07325. and United States patent application 09/054.916, now United States Patent 6.124.278: for Benzoyl Piperidinc/Pyrrolidinc ampakines PCI patent application PCT/US96/07607, and United 10 States patent application Serial No. 08/458367. Filed 2 June 1995. now United States Patent 5,650.409: For betrzoxazine ampakines-PCT patent application. Serial No, PCT/US97/05184, United States patent application. Serial No. 08/624,335. now United States Patent 5,736,543, PCT patent application PCT/US93/06916. and United States patent application, Serial No.
07/919.512. now United States Patent 5_961447; and for carbonylbenzoxazine ampakines-15 PCT patent application PCT/U502/37646. United States Provisional patent application. Serial No. 60/333334. and United States patent application Serial No. 10/495.049. now United States Patent 7,799,913. Each of the foregoing classes and distinct structural groups of ampakine compounds disclosed in the above references are suitable for evaluation to determine operability within the methods and compositions of the invention.
Persons of 20 ordinary skill in the art will recognize that these various compound groups, while being structurally diverse, share common functional characteristics of positive allosteric AMPA
receptor modulation, as described here, and that because of these common functional characteristics, the compounds can be evaluated and determined for their operability according to the inventive discoveries and teachings herein. According to the Examples and
25 other guidance provided here. anti-cancer effective ampakines. for example, can be selected and demonstrated for beneficial. clinical use without undue experimentation.
To practice coordinate administration methods of the invention, the anti-cancer effective AMPAR antagonist compound is co-administered, simultaneously or sequentially.
in a coordinate treatment protocol with one or more of the secondary or adjunctive 30 therapeutic agents contemplated herein. Thus. in certain embodiments the anti-cancer effective AMPAR antagonist compound is administered coordinately with a conventional cancer chemotherapeutic agent using separate formulations or a combinatorial formulation.
Coordinate administration may be done simultaneously or sequentially in either order, and there may be a time period while only one or both (or all) active therapeutic agents individually and/or collectively exert their therapeutic activities. A
distinguishing aspect of all such coordinate treatment methods is that the anti-cancer effective AMPAR
antagonist compound exerts at least some measurably distinct anti-cancer therapeutic activity, yielding a distinct clinical response. in addition to any complementary clinical response provided by the 5 secondary or adjunctive therapeutic agent. Often. the coordinate administration of the anti-cancer effective AMPAR antagonist compound with the secondary or adjunctive therapeutic agent will yield improved anti-cancer therapeutic or prophylactic results in the subject beyond a therapeutic or prophylactic effect elicited by the secondary or adjunctive therapeutic agent alone, which benefit contemplates both direct effects, as well as indirect effects.
10 The anti-cancer effective AM VAR antagonist compounds and pharmaceutical compositions of the present invention may be administered by any means that achieve the contemplated anti-cancer therapeutic or prophylactic purpose. Suitable routes of administration for the compositions of the invention include. but are not limited to, oral, buccal, nasal, aerosol, topical. transderrnal. mucosa'. injectable, and intravenous, as well as 15 all other practicable delivery routes. devices and methods.
The anti-cancer effective AMPAR antagonist compounds of the present invention may be formulated with a pharmaceutically acceptable carrier appropriate for the particular mode of administration employed. Dosage forms of the compositions of the invention include excipients recognized in the art of pharmaceutical compounding as being suitable for 20 the preparation of dosage units as discussed herein. Such excipients include, without limitation. solvates. buffers, binders, fillers, lubricants. emulsifiers, suspending agents, sweeteners, flavorings. preservatives, wetting agents. disintegrants.
effervescent agents and other conventional pharmaceutical excipients and additives.
Anti-cancer effective AMPAR antagonist compounds of the invention will often be 25 formulated and administered in an oral dosage form_ optionally in combination with a carrier and/or other additive(s). Suitable carriers for pharmaceutical formulation of oral dosage forms include. for example. inicrocrystalline cellulose, lactose, sucrose, fructose, glucose, dextrose, or other sugars. di-basic calcium phosphate_ calcium sulfate_ cellulose, methylcellulose. cellulose derivatives. kaolin_ mannitol. lactitol. maltitol.
xvlitol. sorbitol, or 30 other sugar alcohols, dry starch. dextrin. maltodextrin or other polysaccharides, inositol_ or mixtures thereof. Exemplary unit oral dosage forms include ingestible and sublingual liquids, tablets. capsules. and films_ among other options, which may be prepared by any conventional method known in the art. optionally including additional ingredients such as release modifying agents. glidants. cornpression aides. disintegrants.
lubricants. binders.
flavor enhancers, sweeteners and/or preservatives (e.g.. stearic acid, magnesium stearate, talc, calcium stearate. hydrogenated vegetable oils, sodium benzoate. leucine carbowax.
magnesium lauryl sulfate, colloidal silicon dioxide. glyeeryl monostearate, colloidal silica, silicon dioxide, and glyceryl monostearate). Oral dosage forms may further include an 5 enteric coating that dissolves after passing through the stomach, for example, a polymer agent, methacrylate copolymer. cellulose acetate phthalate (CAP).
hydroxypropyl methylcellulose phthalate (11PMCP).. polyvinyl acetate phthalate (PVAP).
hydroxypropyl methylcellulose acetate suceinate (HPMCAS), cellulose acetate trimeliitate.
hydroxypropyl methylcellu lose succinate. cellulose acetate succinate. cellulose acetate hexahydrophthalate, 10 cellulose propionate phthalate_ cellulose acetate rnaleate_ cellulose acetate butyrate, cellulose acetate propionate. copolymer of methylmethacrylic acid and methyl methacrylate.
copolymer of methyl acrylate. methylmethacrylate and methacrylic acid, copolymer of methyl vinyl ether and maleic anhydride (Gantrez ES series). and natural resins such as zein, shellac and copal collophorium.
15 If desired. oral, mucosal. gastric. transdermal. topical and injectable compositions of the invention can be administered in a controlled release form by use of such well known technologies as slow release carriers and controlled release agents.
In certain embodiments the anti-cancer effective AMPAR antagonist compound is administered to patients in an injectable or intravenous (iv) formulation and delivery mode.
20 In illustrative aspects a therapeutic unit dosage of PMP is formulated in a physiological solution amenable for injection or iv delivery to human subjects. for example in an aqueous buffered solution such as saline. Alternative formulations of anti-cancer effective AMPAR
antagonist compounds for administration to patients intravenously, intramuscularly, subcutaneously or intraperitoneally can include nonaqueous sterile injectable solutions and 25 optionally contain anti-oxidants. buffers. bacteriostats and/or solutes which render the formulation isotonic with the blood of the subject, as well as aqueous and non-aqueous sterile suspensions which may include suspending agents and/or thickening agents.
Additional injectable compositions and formulations of the invention may include polymers and other controlled deliver) additives or carriers for extended release following administration.
30 Parenteral preparations may be solutions, dispersions or emulsions suitable for such administration. Extemporaneous injection solutions. emulsions and suspensions may be prepared from sterile powders. granules and tablets. Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose. or an appropriate fraction thereof, of the anti-cancer effective AMPAR antagonist compound and/or active ingredient(s).
In some embodiments, localized delivery of anti-cancer effective AMPAR antagonist compounds may be achieved by injecting the parenteral formulation directly into an area surrounding a cellular malignancy, directly into a tumor_ into the vasculature supplying a malignancy itself, or into a pleural or peritoneal cavity or cerebrospinal compartment proximal or fluidly 5 connected to a targeted malignancy.
In certain embodiments the methods and compositions of the invention may employ a pharmaceutically acceptable salt of an anti-cancer effective AMPAR antagonist compound, for example an acid addition or base salt of a PMP compound, derivative or analog.
Examples of pharmaceutically acceptable addition salts include inorganic and organic acid 10 addition salts. Suitable acid addition salts are formed from acids which form non-toxic salts.
for example, hydrochloride. hydrobromide. hydroiodide. sulphate, hydrogen sulphate, nitrate, phosphate, and hydrogen phosphate salts. Additional pharmaceutically acceptable salts include, but are not limited to. metal salts such as sodium salts, potassium salts, cesium salts and the like; alkaline earth metals such as calcium salts. magnesium salts and the like;
15 organic amine salts such as triethylamine salts, pyridine salts.
picoline salts, ethanolarnine salts, triethanolamine salts. dicyclohexylamine salts. N1,1\l'-dibenzylethylenediamine salts and the like; organic acid salts such as acetate, citrate, lactate, succinate.
tartrate. maleate.
fumarate. mandelate, acetate. dichloroacetate. trilluoroacetate, oxalate, and formate salts;
sulfonates such as methancsulfbnate. benzenesullonate. and p-toluenesulfonate salts; and 20 amino acid salts such as arginate, asparginate, glutamate_ tartrate_ and gluconate salts.
Suitable base salts are formed from bases that form non-toxic salts. for example aluminum, calcium_ lithium_ magnesium. potassium, sodium, zinc and diethanolamine salts.
In related embodiments, optional salt forms of an anti-cancer effective AMPAR antagonist coin pound will yield enhanced properties. e.g., improved stability. solubility, tolerability, etc.
25 In other detailed embodiments. the methods and compositions of the invention employ prodrugs of the anti-cancer effective AMPAR antagonist compound, e.g., prodrugs of a PMP compound or derivative, or of an intermediary compound, or precursor compound of a PMP compound or derivative. As contemplated herein, prodrugs of anti-cancer effective AMPAR antagonist compounds can include the active compound reversibly linked (e.g., 30 covalent]) bonded) to any carrier compound or moiety that functions to release the active anti-cancer effective AMPAR antagonist compound in vivo (for example to effectively mediate delivery, of more active drug. to enhance in vivo half-life of the drug. or otherwise enhance phannacokineties or pharmacodynamics of the drug following administration.
Examples of prodrugs useful within the invention include esters or amides with hydroxyalkyl or aminoalkyl as a substituent, among many other prodrug constructs known in the art.
The invention will also be understood to encompass methods and compositions comprising biologically active metabolites and in vivo conversion products of the anti-cancer 5 effective AMPAR antagonist compound (either generated in vivo after administration of the compound, or directly administered in the form of the metabolite or conversion product itself). Such secondary active products may result for example from oxidation, reduction, hydrolysis, amidation, esterification and the like. of the administered compound, primarily due to enzymatic processes.
10 Example I
Dose-Dependent Anti-Cancer Activity of Exemplary AMPAR Antagonist Perampanel (PMP) T9G (Cilioblastoma) and Pane- I (pancreatic adenocarcinoma) were obtained from ATCC. They were maintained in DM EM media (ATCC) and supplemented with 10% HIS
15 (ATCC) and 1% Penicillin/Streptomycin and maintained in an incubator at 37 C with 95%
air and 5% CO,.
Reagents PMP was purchased from Medkoo and dissolved in DMSO.
Temozolomide, cisplatin and glutamate were purchased from Sigma and dissolved in complete media on the day of treatment.
20 Cancer Cell Viability Assays T98G or Panel cells were seeded in quadruplicate at a density of 6.000 cells/well in complete DMEM and incubated overnight. T98G
cells were then treated with increasing concentrations of PMP and temozolomide for 72 hours.
Alternatively. panel cells were treated with PMP. cisplatin or glutamate for 48 hours.
Following this incubation. 15u1_, MIS solution (Promega) was added to each well and 25 incubated for a further 2 hours. Plates were read at 490nM using the Fl.x808 microplate reader. Absorbance values of wells with only media were subtracted out as background control. Data were normalized to vehicle-treated cells.
Data analysis Data were analyzed using Microsoft excel using a student's t-test.
One-way ANOVA were also performed using Statplus. King's Synergy formula was used to 30 look far synergistic interactions among PMP and chemotherapies. Alpha value was set at p=0.05.
Results The data presented here unexpectedly reveal that AMPAR antagonists.
exemplified by peramplanel (PMP). induce dose-dependent reductions in cell viability of T98G cells (Fig Ia. ANOVA p<0.0001). The surprisingly potent oneolytic effects of peramplanel are mediated in part by antagonistic activity against A MPAR physiology in AM PAR
positive cancer cell targets. Perampanel exhibited significant inhibitory activities against GRM
cancer cell viability, even at concentrations of 1-10uM. demonstrating the clinical utility of 5 this drug at relevant plasma levels for effective cancer chemotherapy.
PMP additively complements anti-cancer effects of ternozolomide (TMZ) at 30uM, and synergistically potentiates TMZ anti-cancer efficacy at I00uM (Fig lb).
Previous work with pancreatic cancer has suggested that ampakines may be able to reduce cell viability. Thus. the results provided here demonstrating that PMP
dose-10 dependently reduces Panel cell viability (ANOVA p=0.0013). with significant reduction of cell viability seen at 100uM (Fig 2a). are particularly surprising. Although I
OuM PMP did not appear to exert potent oncolytic effect alone at this concentration_ it did significantly enhance oncoly sis in combination with the drug cisplatin. Accordingly, PMP
will be clinically effective to improve cancer treatments of this and other chemotherapeutic agents 15 (Fig 2b). 100uM PMP and 3uM cisplatin also synergistically reduced pancreatic cancer cell viability (Fig 2b).
In yet additional working examples provided here, PMP effectively disrupted the oneogenic activity of exogenous glutamate. thereby inhibiting glutamate-potentiated pancreatic cancer activation (e.g.. as demonstrated by impairment of cancer cell 20 proliferation). In these studies. glutamate concentrations of 100-1000uM
elicited a dose-dependent acceleration of pancreatic cancer cell proliferation (Fig 2c). In test samples panel cells were exposed to ImM glutamate for 15 minutes prior to the addition of PMP to cell culture media. Perampanel addition 15 minutes follow" 11 e. glutamate exposure was sufficient to profoundly disrupt oncogenic activities of glutamate (Hg 2d).
Example!!
Dose-Dependent Anti-Cancer Activity of An Exemplar., AMPAR Antagonist, Perampanel (PMP) Potent anti-cancer efficacy of PMP compounds and other etTective AM PAR
30 antagonists is readily demonstrated using a range of animal models that are well known and wideb. accepted in the art as predictive or anti-cancer activity in humans.
One such model employs subcutaneous xenografts of tumor cells into useful study animals such as mice, to study efficacy of candidate anti-cancer drugs in reducing growth or proliferation of xenoffalted tumor cells in test versus control subjects. These studies can include monitoring of a range of indicia of therapeutic efficacy. for example to demonstrate a dose-dependent decrease (e.g.. based on average values observed in test versus control subjects) in xenografted tumor number, tumor size. tumor metastases, tissue histological and/or biochemical cancer markers (e.g.. from biopsy or necropsy-) blood cancer markers. mortality.
etc. As used herein. cancer "markers- refers to any biomolecule. such as a growth factor, genetic regulatory protein. eytokine_ hormone. receptor. etc.. whose presence.
expression, structure, level or activity is correlated with cancer incidence, severity.
progression, or another etiologic or therapeutic factor indicative of cancer growth. metabolic activity, metastasis. etc.
In useful study protocols relating to central nervous system (CNS) cancers such as glioblastoma (GUM). conventional xenograft study designs may be modified to include intracranial xenografting, to better capitulate clinical conditions of CUM
(see, for example, Ozawa et al.. 2010). In one exemplary study protocol employed herein, modified from Ozawa et al._ we employ 198G cells. a GUM cell line expressing the enzyme MGMT, which functions to repair DNA damage from temozoiomide (Mt). rendering this cell type intrinsically resistant to TMZ chemotherapy. These cells are engineered to express the bioluminescent enzyme luciferase to allow in vivo xenograft detection and quantification. A
study total of 24 mice are used, divided into four study groups of 6 members per group. The mice are anesthetized using ketamine/zylazine on a warming plate to maintain core body temperature. Once anesthetized. the scalp is swabbed with chlorohcxidine and a sagittal incision is made over the parieto-occipital bone. about lem long on the left side. The exposed skull is cleaned using a cotton swab with 3% hydrogen peroxide.
Xenograft cells are provided at a concentration of 300.000-500.000 cells in 3u1_, serum-free media, and this cell suspension is drawn into a syringe and injected at a depth of 3mm into the cortical tissue.
The injection is carried out slowly, over a period of one minute. to localize the xenografted cells focally to specific brain region and prevent dissemination of the cells into the ventricles and spinal cord. After injection., the skull is cleaned with 3% hydrogen peroxide and sterile bone wax is to the incised skull defect. The scalp is drawn over the skull and stapled closed.
Buprenorphine is optionally administered for post-operative pain relief, and recovery time is about 30 minutes.
One week after injection the study subjects are divided into 4 groups and bioluminescent monitoring of the xenografts begins. Group 1 mice receive placebo saline for the duration of the experiment. Group 2 receives 20rng/kg/day TMZ. Group 3 receives 5 or lOmg/kg/day PMP depending on what dose produces a partial effect in monotherapy experiments. Group 4 is a combination group that receives both the TMZ and PMP
treatments. Mice are bioluminescent monitored every 4 days during the study, for example using D-luciferin and an in vivo imaging system such as IVIS-200 (PerkinElmer.
Inc, Norwalk Connecticut) to measure bioluminescent photon release as a quantitative indicator of 5 tumor growth.
These and related studies will demonstrate that PMP and other anti-cancer effective AMPAR antagonists according to the teachings herein potently prevent and treat AMPAR
positive CNS cancers, including CiBM. in mammalian subjects. Particular results will demonstrate a dose-dependent reduction in overall luminescence over an effective course of 10 AMPAR antagonist treatment, correlated with reduced tumor size, reduced tumor cell number and/or reduced xenograft proliferative and/or metastatic capacity mediated by the anti-cancer AMPAR antagonist. for example PMP. PMP and other selected AMPAR
antagonist will also significantly decrease tumor cell survival, viability and proliferation, and increase correlated indicia including time to tumor doubling and tripling, as well as subject 15 survival (e.g.. by time and/or numbers of subjects). in addition to mediating significant therapeutic benefits corresponding to all other anti-cancer activity indicators described herein above In more detailed in vivo protocols. PMP will exhibit significant inhibitory activity against GBM xenograft cell viability, proliferative capacity, tumor growth and metastases at 20 concentrations of I-10uM or greater, i.e.. at plasma levels that are safe and effective for cancer chemotherapy.
In other detailed aspects. PMP will be shown to be combinatorially effective to complement anti-GUM effects of secondary anti-cancer drugs and treatments, for example temozolomide (TMZ). In certain embodiments. PMP will complement. potentiate or even 25 synergistically enhance anti-cancer activities of other drugs. for example to significantly increase overall anti-cancer effects in combination with Tmz, compared to anti-cancer effects mediated by =I'MZ, alone. In these embodiments the combinatorial use of PMP and TMZ, e_g.. at therapeutic dosage levels of PMP between about 30uM-100uMõ
provides for enhanced efficacy of TMZ and lower TMZ dosages with reduced TMZ-associated side 30 effects. an exemplary model of coordinate treatment that will be demonstrable across a range of combinations of AMPAR antagonists and secondary/adjunctive anti-cancer agents and therapies.
In related illustrative protocols the efficacy of anti-cancer AMPAR
antagonists such as PMP is demonstrated in combinatorial usage with a PRMT5 inhibitor, such as EPZ015666.
As recently reported by Braun et al (2017). high grade aliomas may be dependent on deletion of detained introns of oncogenic transcripts for sustained growth and survival. PRMT5 ensures proper splicing of these introns to become mature transcripts useful for production of various oncogenic proteins. Inhibition of PRMT5 with [PZ015666 reportedly mediates 5 oncostatic effects against GBM. In one illustrative study here, the foregoing intraeranial xenograft study design is adapted to include one individual test group of 6 mice receiving 100mg/kg/day EPZ015666. one group treated with I Omg/kg/day PMP. and a combinatorial group treated with both EPZ015666 and PMP. Bioluminescent imaging and other measures of anti-cancer efficacy will demonstrate that PMP is anti-cancer effective alone, and 10 combinatorially effective (e.g.. complementary, additive. potentiating or synergistic) in coordinate administration with EPZO I 5666.
In other illustrative protocols of the invention the efficacy of anti-cancer AMPAR
antagonists such as PMP is demonstrated in combinatorial methods with tumor treating fields. Recent studies report that electrical fields using insulated electrodes applying 15 frequencies of 200kliz can inhibit cell cycle progression in GBM cells (see. e.g., Kirson et al.
2007; and Stupp et al. 2015). In an exemplary study here. the intracraniai xenograft protocol is adapted to include one individual test group of 6 mice receiving an external insulated electrode closest to the area of the xenograk applying a 200kIlz current for the duration of the study, one group treated with 10mg/kg/day PMP. and a combinatorial group treated with 20 both therapies. Bioluminescent imaging and other measures of anti-cancer efficacy will demonstrate that PMP is anti-cancer etTective alone and combinatorially effective in coordinate administration with tumor treating fields.
In other exemplary protocols of the invention the efficacy of anti-cancer AMPAR
antagonists such as PMP is demonstrated in combinatorial therapies employing proteins that 25 interfere with telomere function of tumors. for example the TRF I
inhibitor [TP-47037. Due to rapid proliferation of most tumors. tumor cells are particularly vulnerable to DNA damage that can result in cell death. Telomeres are the caps of chromosomes made of repetitive DNA. which serve to prevent protein-coding DNA loss or damage during cell division.
Several proteins are implicated in maintaining telomeres. one of which is a protein designated 30 TRH. Recent studies report that pharmacological or genetic ablation of this TRF I reduces tumor formation and growth in animal models (see, e.g._ Bejarano et al. 2017).
In one report.
75mg/kg of ETP-47037 prevented tumor growth in mice.. In an illustrative protocol here. the intracranial xenograft protocol above is adapted to include one test group of mice receiving a therapeutic dosage of 75mg/kg of VIP-47037. one group treated with I
Orng/kg/day PMP. and a combinatorial group treated with both therapies. Bioluminescent imaging and other measures of anti-cancer efficacy VIII demonstrate that PMP is anti-cancer effective alone and combinatorially effective in coordinate administration with ETP-47037.
Additional studies are contemplated to show that combinatorial treatment with PMP provides for lower dosing of the ETP-47037 to achieve the same or greater clinical benefits, with fewer side effects (e.g.. wherein a comparable. partial anti-cancer effect as exhibited by 75mg/kg is observed in combination with PMP at reduced effective dosages of ETP-47037 of 25-50mg/kg or lower).
In another exemplary combination treatment model of the invention, the efficacy of anti-cancer AMPAR antagonists such as PMP is demonstrated in coordinate protocols with a transcription inhibitor, such as terameprocol. Terameprocol is a global transcription inhibitor that affects proliferation. apoptosis and drug resistance, currently being clinically evaluated for treatment of GBM (Grossman et al. 2012). In one representative study the intracranial xenograft study includes one test group of mice treated with 20mg/kg/day Terameprocol. one group treated with 10mg/kg/day,. PMP. and a combinatorial group treated with both therapies.
Bioluminescent imaging and other measures of anti-cancer efficacy will demonstrate that PMP is anti-cancer effective alone and combinatorially effective in coordinate administration with Terameprocol. Additional studies will show that combinatorial treatment with PMP
provides for lower dosing ofTerameprocol to achieve the same or greater clinical benefits.
with fewer side effects.
In yet additional combinatorial treatment methods of the invention, the efficacy of anti-cancer AMPAR antagonists such as PMP is demonstrated in coordinate protocols with NEK2 inhibitors. Recent studies report that EZH2 is vital for maintaining glioma stem cells, a subset of glioma cells that are responsible for chemo- and radiotherapy resistance due to their ability to regenerate new tumor cells after existing tumor cells are destroyed. NEK2 is responsible for guarding EZH2 against premature breakdown, allowing EZH2 to exert a longer and more robust oncogenic effect. Recent studies report that an inhibitor of NEK2, Cmp3a. exerts anti-cancer effects as demonstrated by prolongation of cancer survival time in mice (Wang et al. 2017). According to the modified study protocol here one group of mice receives I Oing.kg 'day Cmp3a. one group received IOm/kg/day PMP. and a combinatorial group is treated with both therapies. Bioluminescent imaging and other measures of anti-cancer efficacy will demonstrate that prvir is anti-cancer effective alone and combinatorially effeetke in coordinate administration with NEK2 inhibitors such as Cmp3a.
Additional studies will show that combinatorial treatment with PMP provides for lower dosing of NEK3 inhibitors to achieve the same or greater clinical benefits, with fewer side effects.
Example III
Anti-Cancer Activity of AMPAR Antagonists In Combination with Standard Of Care (SOC), Glioma Treatment 5 In exemplary clinical protocols of the invention, anti-cancer effective AMPAR
antagonist treatment will be combined with secondary anti-cancer therapy comprising standard of care (SOC) glioma treatments. In one illustrative example, patients are initially treated with SOC maximal safe surgical resection_ followed by an aggressive SOC
chemoradiation protocol. For the first 6 weeks of treatment, patients receive 75mg/m2/day of 10 Temozolomide (Temodar) starting one hour prior to radiation treatment.
Patients additionally receive 200cGy focal radiation per day for the First live days of the week over a 6 week timespan (30 fractions). for a total of 60Gy radiation. Radiation targets the tumor area as well as surrounding edema plus a I em margin. I month after the last radiation treatment, patients are administered I 50-200mg/m2/day, temozolomide for the first 5 days of every 15 month followed by 3 weeks rest as well as antiemetie prophylaxis treatment as needed.
Treatments are stopped ifplatelet count drops below I00.000/uL. or if there is evidence of disease progression or severe treatment-related toxicity (Grossman et at 2009). In combination with the SOC glioma treatment outlined above, patients receive 8mg peramplanel orally 1 hour prior to the first radiation session. Perampanel is further 20 administered once per day, and weekly titrated up 2 mg/day until patients receive the maximally tolerated approved dose (mTD) of 12 mg (Gidal et al, 2015) (though this range can be adjusted up or down based on patient-specific tolerance and other clinical factors determined by the managing physician). Within illustrative methods for treating GBM, patients receive the MT[) throughout an initial 6-week treatment period, during the 1 month 25 SOC rest period, and while patients are taking maintenance Temodar.
Patients are maintained on perampanel treatment as determined by the managing physician, unless disease progression or evidence of perarnplanel-related toxicity is observed_ Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-glioma therapy.
30 Example IV
Anti-Cancer Activity of AMPAR Antagonists In Combination with Levetiracetam Co-Treatment In additional clinical examples_ patients are treated concomitantly with an AMPAR
antagonist such as peramplanel and Levetiracetam (Keppra). which has been shown to augment temozolonnide efficacy (13obustue et al. 2010) and reduce aggression-related adverse events in patients taking perampanel (Kanemura et al, 2019: Kim et al. 2015).
Patients are administered perampanel as described above along with 500mg levetiracetam 1 hour prior to the first radiation session. Levetiracetam is administered twice a day. the second time being at night before bed. Within illustrative methods for treating GBM, patients receive 200-500mg levetiracetam twice a day throughout the first 6-week treatment period, during the 1 month rest period, and while patients are taking maintenance Temodar. Patients continue to receive leveliracetain and perampanel unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
Example V
Anti-Cancer Activity of AMPAR Antagonists In Combination with NMDA Receptor Antagonist Co-Treatment In other clinical protocols useful within the invention, patients are treated concomitantly with an N-methyl-D-aspartate (NMDA) receptor antagonist, such as memantine. Memantine has been reported to exert anti-cancer effects, possibly by abrogating constitutively active growth pathways in cancer (Stepulak et al, 2005: Maraka et al, 2019).
Patients receive perampanel along with 5-20mg memantine orally prior to the first radiation session. Within illustrative methods for treating GBM. perampanel and memantine are administered once a day throughout the first 6-week treatment period, during the 1 month rest period, and while patients are taking maintenance Temodar. Patients are maintained on memantine and perampanel unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
In addition to memantine. ketamine. an NMDA-antagonist used in the setting of pharrnacoresistant depression. may also be used. Ketamine is given at doses ranging from 5-500mg/day and started prior to the first radiation session. Ketamine and its active metabolite hydroxynorketamine (Zanos et al. 2016) may provide anti-cancer benefits (Malsy et al.
2015). and will be a beneficial adjunct within the methods of the invention, for example to complement standard of care + perampanel treatments.
Example VI
Anti-Cancer Activity of AMPAR Antagonists In Combination with Riluzole/Troriluzole Co-Treatment Additional clinical methods of the invention employ an AMPAR antagonist such as 5 perampanel coordinately administered with Riluzole/ troriluzole (see.
e.g.. Khan et al, 2019).
Patients receive perampanel as above in coordinate treatment with with 20-50tng Riluzole/troriluzole orally prior to the first radiation session. Within illustrative methods for treating GBM. perampanel and Rilwole/troriluzole are administered once a day throughout the first 6-week treatment period, during the I month rest period, and while patients are 10 taking maintenance Temodar. Patients are maintained on Riluzole/troriluzole and perampanel unless disease progression or evidence of drug-related toxicity is observed.
Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
Example VII
15 Anti-Cancer Activity of AMPAR Antamonists In Combination with CSF1R Inhibitors Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with a colony stimulating factor 1 receptor (CSF I R) inhibitor such as PLX3397 (plexidartinib) or PLX5562 (see. e.g., Yan et al, 2017; Butowski 20 et al. 2016). Patients are administered perampanel as above in coordinate treatment with 100-1000 mg PLX3397 orally prior to the first radiation session. Within illustrative methods for treating GUM. perarnpanel and PLX3397 are administered together or separately once a day throughout the first 6-week treatment period, during the 1 month rest period, and while patients are taking maintenance Temodar. Patients are maintained on PLX3397 and 25 perampancl unless disease progression or evidence of drug-related toxicity is observed.
Subjects treated according to this combinatorial protocol .µ ill show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy. While CSH R
inhibition is reported to provide pre-clinical anti-cancer benefitsresults (Patwardhan et al, 2014: Yan et al. 2017: Quail et al_ 2016). most pre-clinical models of different types of 30 cancer demonstrate acquired resistance throughout this treatment (Patwardhan et al.. 2014;
Quail et al. 2016). In particular. for brain cancer, it has been shown that insulin-like growth factor I (IGF I ) induces glioma rebound in CSH R inhibitor-treated mice (Quail et al, 2016).
Surprisingly. AMPA-glutanaate antagonism according to the methods described here will negate oncogenic effects of !GEL and AMPA-glutamate antagonism will complement with CSF I R inhibition to lower tumor burden in co-treated subjects. In more detailed aspects of the invention, it is noted that P'EX3397 may inhibit PDGFRB signaling in cancer 5 (Patwardhan et al. 2014). and that PDGF'RB reportedly coordinates an anti-oxidant program in cancer through NRF2 transcription (Yang et al. 2018; Nanjaiah et al. 2019).
On this basis, according to the teachings herein. PLX3397 will be beneficially combined with glutamate antagonists like memantine. within AMPAR antagonist methods of the invention, to bolster combined efficacy by suppressing an anti-oxidant program, e.g., in glioma cells.
10 Example VIII
Anti-Cancer Activity of AMPAR Antagonists In Combination with Anti-Malarial Drugs Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with one or more anti-malarial drugs such as 15 chloroquine, hydroxychloroquine. prima/wine and mefloquine (see. e.g., Johnson et al, 2015;
Liu et al, 2016: Maraka et al, 2019). In exemplary protocols. patients receive perampanel as above along with 250mg mefloquine orally prior to the first radiation session.
Within illustrative methods for treating GBM. Metloquine is administered once every two days throughout the first 6-week treatment period, during the I month rest period, and while 20 patients are taking maintenance Temodar. Patients are maintained on the anti-malarial and perampanel unless disease progression or evidence of drug-related toxicity is observed.
Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
Example VIX
25 Anti-Cancer Activity of AMPAR Antagonists In Combination with Metformin/Phenformin Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with metformin (see, e.g.. Benjamin et al.. 2016:
Maraka et al. 2019). Patients receive perampanel as above along with 500-2000mg 30 metformin orally prior to the first radiation session. In exemplary protocols for treating GBM, peranapanel and metformin are administered once a day throughout the first 6-week treatment period., during the I month rest period, and while patients are taking maintenance Temodar. Patients are maintained on the metform in and perampanel unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or 5 other conventional anti-cancer therapy.
Example X
Anti-Cancer Activity of AMPAR Antagonists In Combination with PD-I Inhibitor Treatment Additional clinical methods of the invention employ an AMPAR antagonist such as 10 perampanel coordinate!) administered with anti-cancer biologics including programmed cell death protein I (PD-1) inhibitors, such as pembroliitimab or nivolumab (see, e.g., Nghiem et al. 2016: Motzer et al. 2015). Resistance to PD- I antagonism has been attributed to TNF-a production in the tumor microenvironment (Neubert et al. 2018). Since Ampa-glutamate antagonism has been shown to reduce TNF-a secretion in a model of intraventricular 15 hemorrhage (Dohare et al. 2016). AMPAR antagonist treatment according to the invention will augment the efficacy of PD- I inhibitors. In exemplary protocols, patients are administered perampanel as above, in conjunction with I-3mg/kg pembrolizumabinivolumab intravenously prior to the first radiation session. Within illustrative methods for treating GBM. patients then receive pembrolizumabinivolumab every 2 weeks throughout the first 6-20 week treatment period. during the 1 month rest period, and while patients are taking maintenance Temodar. Treatment is continued thusly unless disease progression or evidence of drug-related toxicity appears. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
25 Example XI
Anti-Cancer Activity of AMPAR Antagonists In Combination with PD- I Inhibitor + CSF I R Inhibitor Treatment Within more detailed examples. AMPAR antagonists such as perampanel are coordinately administered with PD- I inhibitors, and also with CSF I R
inhibitors. Notably, 30 while PD-I inhibitors reportedl) exhibit robust efficacy in some patients, they appear to have little to no therapeutic effects in other patients. Recently. it has been suggested that CSF I
and TN F-a secretion by tumor cells may stanch the efficacy of' PD-I therapy (Neubert et al, 2018). As disclosed herein, patients be treated with a combination of AMPAR
antagonists PD-1 inhibitors and CSF I R inhibitors (e.g.. with perampancl, pembrolizumab.
and PLX3397) will benefit by reduced CSF1 signaling in the tumor mieroenvironment, combined with 5 ampa-glutannate antagonist repression of `INF signaling (see, e.g..
Dohare et al, 2016).
negating PD-1 inhibitor resistance to yield enhanced clinical benefits over SOC or other conventional anti-cancer therapy.
,Exaniple XII
Anti-Cancer Activity of AMPAR Antagonists In Combination with 10 Clemastine Fumarate Co-Treatment Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with clemastine fumarate (see, e.g., Diibbeling et al, 2013: Le Joncour et al. 2019). Patients are administered perm-vane' as above along with 0.5-2.68mg clemastine fumarate orally prior to the first radiation session. In illustrative protocols 15 for treating GBM, perampanel and clemastine are taken once a day throughout the first 6-week treatment period_ during the I month rest period, and while patients are taking maintenance Temodar. Patients are maintained on the clemastine fumarate and perampanel unless disease progression or evidence of drug-related toxicity is observed.
Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits 20 over SOC or other conventional anti-cancer therapy.
Example XIII
Anti-Cancer Activity of AMPAR Antagonists In Combination with SSRI Co-Treatment Additional clinical methods of the invention employ an AMPAR antagonist such as 25 perampanel coordinately administered with one or more selective serotonin reuptake inhibitors (SSR1s) (see. e.g.. Sun et al. 2018: Huang et al. 2011: I,in et al.
2010: Liu et al, 2015: Yuan et al. 2018: Raabe & Gentile. 2008). In exemplary protocols for treating CiBM, patients are administered perampanel along with the SSRI(s) orally prior to the first radiation session, then once a day throughout the first 6-week treatment period, during the 1 month rest 30 period, and while patients are taking maintenance Temodar. Patients are maintained on the SSRI and perampanel unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
Example XIV
Anti-Cancer Activity of AMPAR Antagonists In Combination with 5 TCA Co-Treatment Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with one or more tricyclic antidepressants (TCAs) (see, e.g._ Jahchan et al, 2013; Jeon et al. 2011: Raabe & Gentile, 2008;
Reynolds & Miller, 1988: Semagor et al_ 1989: Stoll et al. 2007). Patients receive perampanel along with the 10 TCA(s) orally prior to the first radiation session. In exemplary protocols for treating GBM, the perampanel and TCA are then each administered once a day throughout the first 6-week treatment period, during the I month rest period_ and while patients are taking maintenance Temodar. Patients are maintained on the TCA and perampanel unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this 15 combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
Example XV
Anti-Cancer Activity of AMPAR Antagonists In Combination with Ampakine Co-Treatment 20 Additional clinical methods of the invention employ an AMPAR
antagonist such as perampanel coordinately administered with one or more positive allosteric AMPA
receptor modulators (Ampakines). In exemplary protocols. patients are administered perampanenl in combination with one or more ampakines. such as 2.3.6a.7.8.9-hexahydro-1 I H-l.4-dioxino[2.3-glpyrrolo[2.1-b][ 1.3Jbenzoxa7ine-I 1-one (-CX614-) (see. e.g., Radin et al.
25 2018). Though ampakines are thought to augment AMPA-mediated currents in neurons, they have also been reported to induce AMPA receptor desensitization and down regulation via endocytosis and degradation after prolonged treatment (Jourdi et al_ 2005), whereby they may serve as functional antagonists. Within illustrative methods for treating GBM, patients are administered perampanel along with CX614 or another amplakine orally prior to the first 30 radiation session. then once a day throughout the first 6-week treatment period, during the 1 month rest period, and while patients are taking maintenance Temodar. Patients are maintained on the ampakine(s) and perampanel unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
Example XVI
Anti-Cancer Activity of AMPAR Antagonists In Combination with Cannabinoid Co-Treatment Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with one or more cannabinoids, for example tetrahydroeannabinol (-111C) and/or cannabidiol (CBD) (see. e.g.. Scott et al, 2014; Mareu et al. 2010; Shrisastava et al. 2011). In exemplary protocols for treating GBM, patients are administered perampanel along with I 00-600mg CID and 1-100ing T-IC prior to the first radiation session. then once a day throughout the first 6-week treatment period, during the 1 month rest period, and while patients are taking maintenance Ternodar.
Patients are maintained on the cannabinoid and perampanel therapy unless disease progression or evidence of drug-related toxicit) is observed. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy. For treatment of GBM. cannabinoids have been reported to potent effects on glioma stem cells (Lepez-Valero et al_ 2018). Considering that AMPA
receptors are overexpressed on glionia stem cells (Oh et al. 2012). the combinatorial treatment methods and compositions described here w ill sensitize resistant tumor cells to the DNA-damaging effects of Ternodar and radiation therapy (McLendon et al_ 2006;
Chen et al, 2012) and thereby enhance clinical benefits. Further. cannabinoids reportedly exert oncolytic effects through induction of harmful reactive oxygen species (Shrivastava et al, 2011;
Nanjaiah et al, 2019). whereby the methods and compositions of the invention combining cannabinoids with glutamate antagonists will negate antioxidant defenses in cancer cells and enhance clinical benefits. particularly in elioma patients.
Example XVI
.Anti-Cancer Activitv of AMPAR Antagonists In Combination with Distil firam Co-Treatment Yet additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with disulfirarn (see, e.g., Lun et al, 2016; Triscon et al, 2012). Disulfiram targets cancer stem cells and reportedly inhibits MGMT to boost efficacy of Temodar (Paranjpe et al. 2014). Within the methods of the invention, both 5 disulfiram and perampanel augment Temodar's efficacy and refine targeting of cancer cells, yielding surprisingly enhanced benefits for treating SOC treatment-resistant cancers. Within exemplary methods for treating GBM. patients are administered perampanel along with 50-500mu disulfiram orally prior to the first radiation session, then once daily throughout the first 6-week treatment period. during the 1 month rest period, and while patients are taking 10 maintenance Temodar. Patients are maintained on the perampanel and disulfiram unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
The instant description and examples are provided lor illustration, and those skilled in 15 the art will realize that the invention extends to additional embodiments and aspects following the teachings herein, and is therefore not limited except as by the appended claims.
References 1. Grossman, S. A., Ye, X., Chamberlain. M., Mikkelsen, T.. Batchelor, T., Desideri, S., ... Fine, H. A. (2009). Talampanel with standard radiation and temozolomide in patients with newly diagnosed glioblastorna: A multicenter phase 11 trial.
Journal of 5 Clinical Oncology, 27(25), 4155-416 I .
2. Gidal. B. E., Laurenza. µA.. Hussein. Z., Yang, H., Fain, It, Edelstein, J., ... Ferry, J.
(2015). Perampanel efficacy and tolerability with enzyme-inducing AEDs in patients with epilepsy. Neurology, 84(19), 1972-1980.
3 Bobustuc, G. C., Baker, C. H.. Limaye. A., Jenkins, W. D., Pearl, G., Avgeropoulos.
10 N. G., & Konduri. S. D. (2010). Levetiracetam enhances p53-mediated MGMT
inhibition and sensitizes glioblastoma cells to temozolomide. Neuro-Oncology, 12(9), 917-927.
4 Kanemura, H., Sano, F., & Aihara. M. (2019).
Usefulness of perampanel with concomitant levetiracetam for patients with drug-resistant epilepsy. European Journal 15 q-Paediatric- Neurology, 23(1). 197-203.
5. Kim, Y._ Kim, it Jot), J., Han. J. H.. Kim, Y.
J., Kim. I. A._ . Kim, C. (2015).
Survival benefit of levetiracetam in patients treated with concomitant chemoradiotherapy and adjuvant chemotherapy with temozolomide for glioblastoma multiforme. Cancer. 121(17). 2926-2932.
20 6 Stepulak, A.. Sifringer, M. Rzeski. W., Endesfelder, S.. Gratopp, A., Pohl, E. E, lkonomidou. C. (2005). NMDA antagonist inhibits the extracellular signal-regulated kinase pathway and suppresses cancer growth. Proceedings of the National Academy .Sc.lences the United States of America, 102(43), I 5605- l 5610.
7 Maraka, S., Groves, M. D., Mammoser. A. G., Melguizo-Gavilanes, 1., Conrad, C. A., 25 Tremont-Lukats, I. W., Penas-Prado, M. (2019). Phase 1 lead-in to a phase 2 factorial study of temozolomide plus memantine, mefloquine, and metformin as postradiation adjuvant therapy for newly diagnosed glioblastoma. Cancer, 125(3), 424-433.
8 Zanos, P., Moaddel. It. Morris. P. J., Georgiou, P.. Fischell, J., Elmer, G. 1., .
30 Gould, T. D. (2016). NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature, 533(7604), 481-486.
9 Malsy, M.. Gebhardt, K.. (lather, M., Wiese. C.. Graf, B.. & Bundscherer, A.
(2015).
Effects of ketamine. s-ketamine. and MK 801 on proliferation, apoptosis. and necrosis in pancreatic cancer cells. BAK' Anesthesiologv, 15(1). I 11-118.
35 to Khan, A. J., LaCava, S., Mehta, M., Schiff. D., Thandoni. A., Jhawar, S., ... Chen, S.
(2019). The glutamate release inhibitor riluzole increases DNA damage and enhances cvtotoxicity in human glioma cells_ in vitro and in vivo. Oncotarget, /0(29), 2834.
it Van, D., Kovyal, J., Akkari_ L., Schuhmacher_ A. J., Huse. J. T.. West, B.
L., & Joyce, 40 J. A. (2017). Inhibition of colony stimulating factor-1 receptor abrogates microenvironment-mediated therapeutic resistance in gliomas. Oncogene, 36(43).
6049-6058.
12 Butowski, N., Colman, H., De Groot, J. F.. Omuro, A. M., Nayak, L., Wen, P.
Y., . .
Prados. M. (2016). Orally administered colony stimulating factor 1 receptor inhibitor 45 PLX3397 in recurrent glioblastoma: An ivy foundation early phase clinical trials consortium phase It study. Nettro-Oncoloff, /8(4). 557-564.
13. Patwardhan. P. P., Surriga, 0.. Beckman, M. J., de Stanehina. E., Dematteo, R. P., Tap. W. D.. & Schwartz. G. K. (2014). Sustained inhibition of receptor tyrosine kinases and macrophage depletion by PLX3397 and rapamycin as a potential new approach for the treatment of MPNSTs. Clinical Cancer Research 20(12), 3 I 46-3158.
14. Yan, D., Kowal, J., Akkari, L., Schuhmacher, A. J., Huse, J. T., West, B.
L., & Joyce, J. A. (2017). Inhibition of colony stimulating factor-I receptor abrogates 5 microenvironment-mediated therapeutic resistance in gliomas.
Oncogene, 36(43), 6049-6058.
15. Quail, D. F., Bowman, R. L., Akkari, L., Quick, M. L., Schuhmacher, A. J., Huse, J.
T.,.. . Joyce, J. A. (2016). The tumor microenvironment underlies acquired resistance to CSF-I R inhibition in gliomas. Science. 352(6288).
10 16. Stepulak, A., Sifringer, M., Rzeski, W., Brocke, K., Gratopp, A., Pohl, E. F.....
lkonomidou, C. (2007). AMPA antagonists inhibit the extracellular signal regulated kinase pathway and suppress lung cancer growth. Cancer Biology & Therapy, 6(12), 1908.
17 Yang, Z.. Yang. Y., Deng. Y., Chen. Y., Chen. X., Zhang. L..... Liu, B.
(2018).
15 Inhibition of PDGFR by CP-67345I induces apoptosis and increases cisplatin cytotoxicity in NSCI.0 cells via inhibiting the Nr12-mediated defense mechanism. 7in/eulogy Letters, 295, 88-98.
ia Nanjaiah, N. D., Ramaswamy, P., Goswarni. K., Hurmath Fathima, K., &
Borkotokey, M. (2019). Survival of glioblastoma cells in response to endogenous and 20 exogenous oxidative challenges: Possible implication of NMDA
receptor mediated regulation of redox homeostasis. Cell Biology International, 11193. 1-10.
is. Johnson, C. E., Hunt, D. K., Wiltshire, M., Herbert, T. P., Sampson, J.
R., Errington, R. J.,.,. . Tee, A. R. (2015). Endoplasmic reticulum stress and cell death in mTORC1-overactive cells is induced by nelfinavir and enhanced by chloroquine.
Molecular 25 Oncofoff, 9(3), 675-688.
20 Liu, Y., Chen. S... Xue. R.. Zhao, J.. & Di. M. (2016). Mefloquine effectively targets gastric cancer cells through phosphatase-dependent inhibition of P13K/Akt/inTOR
signaling pathway. Biochemical and Biophysical Research Communications, 470(2), 350-355.
30 21 Benjamin, D., Colombi, M.. Hindupur, S. K.. Betz. C.. Lane* H. A., EI-Shemerly, M.
Y. M..... Hall, M. N. (2016). Syrosingopine sensitizes cancer cells to killing by metformin. Science Advances. 2(12), el60 I 756-el 601 756.
22 Nghiem. P. T., Bhatia. S., Lipson. E. J.. Kudchadkar, R. It.. Miller, N.
J.., Annamalai, L..... Cheever, M. A. (2016). PD-1 blockade with pembrolizunaab in advanced 35 merkel-cell carcinoma. The New England Journal of Medicine, 374(26), 2542-2552.
23. Motzer, R. J., Escudier, B., McDermott. D. F., George, S., Hammers, H. J., Srinivas, S., .. CheckMate 025 Investigators. (2015). Nivolumab versus everolimus in advanced renal-cell carcinoma. The Neu, England Journal of Medicine. 373(19), 1803-1813.
40 24 Neubert. N. J., Schmittnaegel, M., Bordry, N., Nassiri, S., Wald, N., Martignier, C.,..
. Speiser. D. E. (2018). T cell-induced CSF I promotes melanoma resistance to PDI
blockade. Science Translational Medicine. 10(436), 1-14.
25 Dohare. P., Zia. M. T.. Ahmed. E.. Ahmed. A.. Yadala. V.. Schober, A. L., .
.
Ballabh, P. (2016). AMPA-kainate receptor inhibition promotes neurologic recovery 45 in premature rabbits with intraventricular hemorrhage...!
Neuravci. 36(11), 3363-3377.
To practice coordinate administration methods of the invention, the anti-cancer effective AMPAR antagonist compound is co-administered, simultaneously or sequentially.
in a coordinate treatment protocol with one or more of the secondary or adjunctive 30 therapeutic agents contemplated herein. Thus. in certain embodiments the anti-cancer effective AMPAR antagonist compound is administered coordinately with a conventional cancer chemotherapeutic agent using separate formulations or a combinatorial formulation.
Coordinate administration may be done simultaneously or sequentially in either order, and there may be a time period while only one or both (or all) active therapeutic agents individually and/or collectively exert their therapeutic activities. A
distinguishing aspect of all such coordinate treatment methods is that the anti-cancer effective AMPAR
antagonist compound exerts at least some measurably distinct anti-cancer therapeutic activity, yielding a distinct clinical response. in addition to any complementary clinical response provided by the 5 secondary or adjunctive therapeutic agent. Often. the coordinate administration of the anti-cancer effective AMPAR antagonist compound with the secondary or adjunctive therapeutic agent will yield improved anti-cancer therapeutic or prophylactic results in the subject beyond a therapeutic or prophylactic effect elicited by the secondary or adjunctive therapeutic agent alone, which benefit contemplates both direct effects, as well as indirect effects.
10 The anti-cancer effective AM VAR antagonist compounds and pharmaceutical compositions of the present invention may be administered by any means that achieve the contemplated anti-cancer therapeutic or prophylactic purpose. Suitable routes of administration for the compositions of the invention include. but are not limited to, oral, buccal, nasal, aerosol, topical. transderrnal. mucosa'. injectable, and intravenous, as well as 15 all other practicable delivery routes. devices and methods.
The anti-cancer effective AMPAR antagonist compounds of the present invention may be formulated with a pharmaceutically acceptable carrier appropriate for the particular mode of administration employed. Dosage forms of the compositions of the invention include excipients recognized in the art of pharmaceutical compounding as being suitable for 20 the preparation of dosage units as discussed herein. Such excipients include, without limitation. solvates. buffers, binders, fillers, lubricants. emulsifiers, suspending agents, sweeteners, flavorings. preservatives, wetting agents. disintegrants.
effervescent agents and other conventional pharmaceutical excipients and additives.
Anti-cancer effective AMPAR antagonist compounds of the invention will often be 25 formulated and administered in an oral dosage form_ optionally in combination with a carrier and/or other additive(s). Suitable carriers for pharmaceutical formulation of oral dosage forms include. for example. inicrocrystalline cellulose, lactose, sucrose, fructose, glucose, dextrose, or other sugars. di-basic calcium phosphate_ calcium sulfate_ cellulose, methylcellulose. cellulose derivatives. kaolin_ mannitol. lactitol. maltitol.
xvlitol. sorbitol, or 30 other sugar alcohols, dry starch. dextrin. maltodextrin or other polysaccharides, inositol_ or mixtures thereof. Exemplary unit oral dosage forms include ingestible and sublingual liquids, tablets. capsules. and films_ among other options, which may be prepared by any conventional method known in the art. optionally including additional ingredients such as release modifying agents. glidants. cornpression aides. disintegrants.
lubricants. binders.
flavor enhancers, sweeteners and/or preservatives (e.g.. stearic acid, magnesium stearate, talc, calcium stearate. hydrogenated vegetable oils, sodium benzoate. leucine carbowax.
magnesium lauryl sulfate, colloidal silicon dioxide. glyeeryl monostearate, colloidal silica, silicon dioxide, and glyceryl monostearate). Oral dosage forms may further include an 5 enteric coating that dissolves after passing through the stomach, for example, a polymer agent, methacrylate copolymer. cellulose acetate phthalate (CAP).
hydroxypropyl methylcellulose phthalate (11PMCP).. polyvinyl acetate phthalate (PVAP).
hydroxypropyl methylcellulose acetate suceinate (HPMCAS), cellulose acetate trimeliitate.
hydroxypropyl methylcellu lose succinate. cellulose acetate succinate. cellulose acetate hexahydrophthalate, 10 cellulose propionate phthalate_ cellulose acetate rnaleate_ cellulose acetate butyrate, cellulose acetate propionate. copolymer of methylmethacrylic acid and methyl methacrylate.
copolymer of methyl acrylate. methylmethacrylate and methacrylic acid, copolymer of methyl vinyl ether and maleic anhydride (Gantrez ES series). and natural resins such as zein, shellac and copal collophorium.
15 If desired. oral, mucosal. gastric. transdermal. topical and injectable compositions of the invention can be administered in a controlled release form by use of such well known technologies as slow release carriers and controlled release agents.
In certain embodiments the anti-cancer effective AMPAR antagonist compound is administered to patients in an injectable or intravenous (iv) formulation and delivery mode.
20 In illustrative aspects a therapeutic unit dosage of PMP is formulated in a physiological solution amenable for injection or iv delivery to human subjects. for example in an aqueous buffered solution such as saline. Alternative formulations of anti-cancer effective AMPAR
antagonist compounds for administration to patients intravenously, intramuscularly, subcutaneously or intraperitoneally can include nonaqueous sterile injectable solutions and 25 optionally contain anti-oxidants. buffers. bacteriostats and/or solutes which render the formulation isotonic with the blood of the subject, as well as aqueous and non-aqueous sterile suspensions which may include suspending agents and/or thickening agents.
Additional injectable compositions and formulations of the invention may include polymers and other controlled deliver) additives or carriers for extended release following administration.
30 Parenteral preparations may be solutions, dispersions or emulsions suitable for such administration. Extemporaneous injection solutions. emulsions and suspensions may be prepared from sterile powders. granules and tablets. Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose. or an appropriate fraction thereof, of the anti-cancer effective AMPAR antagonist compound and/or active ingredient(s).
In some embodiments, localized delivery of anti-cancer effective AMPAR antagonist compounds may be achieved by injecting the parenteral formulation directly into an area surrounding a cellular malignancy, directly into a tumor_ into the vasculature supplying a malignancy itself, or into a pleural or peritoneal cavity or cerebrospinal compartment proximal or fluidly 5 connected to a targeted malignancy.
In certain embodiments the methods and compositions of the invention may employ a pharmaceutically acceptable salt of an anti-cancer effective AMPAR antagonist compound, for example an acid addition or base salt of a PMP compound, derivative or analog.
Examples of pharmaceutically acceptable addition salts include inorganic and organic acid 10 addition salts. Suitable acid addition salts are formed from acids which form non-toxic salts.
for example, hydrochloride. hydrobromide. hydroiodide. sulphate, hydrogen sulphate, nitrate, phosphate, and hydrogen phosphate salts. Additional pharmaceutically acceptable salts include, but are not limited to. metal salts such as sodium salts, potassium salts, cesium salts and the like; alkaline earth metals such as calcium salts. magnesium salts and the like;
15 organic amine salts such as triethylamine salts, pyridine salts.
picoline salts, ethanolarnine salts, triethanolamine salts. dicyclohexylamine salts. N1,1\l'-dibenzylethylenediamine salts and the like; organic acid salts such as acetate, citrate, lactate, succinate.
tartrate. maleate.
fumarate. mandelate, acetate. dichloroacetate. trilluoroacetate, oxalate, and formate salts;
sulfonates such as methancsulfbnate. benzenesullonate. and p-toluenesulfonate salts; and 20 amino acid salts such as arginate, asparginate, glutamate_ tartrate_ and gluconate salts.
Suitable base salts are formed from bases that form non-toxic salts. for example aluminum, calcium_ lithium_ magnesium. potassium, sodium, zinc and diethanolamine salts.
In related embodiments, optional salt forms of an anti-cancer effective AMPAR antagonist coin pound will yield enhanced properties. e.g., improved stability. solubility, tolerability, etc.
25 In other detailed embodiments. the methods and compositions of the invention employ prodrugs of the anti-cancer effective AMPAR antagonist compound, e.g., prodrugs of a PMP compound or derivative, or of an intermediary compound, or precursor compound of a PMP compound or derivative. As contemplated herein, prodrugs of anti-cancer effective AMPAR antagonist compounds can include the active compound reversibly linked (e.g., 30 covalent]) bonded) to any carrier compound or moiety that functions to release the active anti-cancer effective AMPAR antagonist compound in vivo (for example to effectively mediate delivery, of more active drug. to enhance in vivo half-life of the drug. or otherwise enhance phannacokineties or pharmacodynamics of the drug following administration.
Examples of prodrugs useful within the invention include esters or amides with hydroxyalkyl or aminoalkyl as a substituent, among many other prodrug constructs known in the art.
The invention will also be understood to encompass methods and compositions comprising biologically active metabolites and in vivo conversion products of the anti-cancer 5 effective AMPAR antagonist compound (either generated in vivo after administration of the compound, or directly administered in the form of the metabolite or conversion product itself). Such secondary active products may result for example from oxidation, reduction, hydrolysis, amidation, esterification and the like. of the administered compound, primarily due to enzymatic processes.
10 Example I
Dose-Dependent Anti-Cancer Activity of Exemplary AMPAR Antagonist Perampanel (PMP) T9G (Cilioblastoma) and Pane- I (pancreatic adenocarcinoma) were obtained from ATCC. They were maintained in DM EM media (ATCC) and supplemented with 10% HIS
15 (ATCC) and 1% Penicillin/Streptomycin and maintained in an incubator at 37 C with 95%
air and 5% CO,.
Reagents PMP was purchased from Medkoo and dissolved in DMSO.
Temozolomide, cisplatin and glutamate were purchased from Sigma and dissolved in complete media on the day of treatment.
20 Cancer Cell Viability Assays T98G or Panel cells were seeded in quadruplicate at a density of 6.000 cells/well in complete DMEM and incubated overnight. T98G
cells were then treated with increasing concentrations of PMP and temozolomide for 72 hours.
Alternatively. panel cells were treated with PMP. cisplatin or glutamate for 48 hours.
Following this incubation. 15u1_, MIS solution (Promega) was added to each well and 25 incubated for a further 2 hours. Plates were read at 490nM using the Fl.x808 microplate reader. Absorbance values of wells with only media were subtracted out as background control. Data were normalized to vehicle-treated cells.
Data analysis Data were analyzed using Microsoft excel using a student's t-test.
One-way ANOVA were also performed using Statplus. King's Synergy formula was used to 30 look far synergistic interactions among PMP and chemotherapies. Alpha value was set at p=0.05.
Results The data presented here unexpectedly reveal that AMPAR antagonists.
exemplified by peramplanel (PMP). induce dose-dependent reductions in cell viability of T98G cells (Fig Ia. ANOVA p<0.0001). The surprisingly potent oneolytic effects of peramplanel are mediated in part by antagonistic activity against A MPAR physiology in AM PAR
positive cancer cell targets. Perampanel exhibited significant inhibitory activities against GRM
cancer cell viability, even at concentrations of 1-10uM. demonstrating the clinical utility of 5 this drug at relevant plasma levels for effective cancer chemotherapy.
PMP additively complements anti-cancer effects of ternozolomide (TMZ) at 30uM, and synergistically potentiates TMZ anti-cancer efficacy at I00uM (Fig lb).
Previous work with pancreatic cancer has suggested that ampakines may be able to reduce cell viability. Thus. the results provided here demonstrating that PMP
dose-10 dependently reduces Panel cell viability (ANOVA p=0.0013). with significant reduction of cell viability seen at 100uM (Fig 2a). are particularly surprising. Although I
OuM PMP did not appear to exert potent oncolytic effect alone at this concentration_ it did significantly enhance oncoly sis in combination with the drug cisplatin. Accordingly, PMP
will be clinically effective to improve cancer treatments of this and other chemotherapeutic agents 15 (Fig 2b). 100uM PMP and 3uM cisplatin also synergistically reduced pancreatic cancer cell viability (Fig 2b).
In yet additional working examples provided here, PMP effectively disrupted the oneogenic activity of exogenous glutamate. thereby inhibiting glutamate-potentiated pancreatic cancer activation (e.g.. as demonstrated by impairment of cancer cell 20 proliferation). In these studies. glutamate concentrations of 100-1000uM
elicited a dose-dependent acceleration of pancreatic cancer cell proliferation (Fig 2c). In test samples panel cells were exposed to ImM glutamate for 15 minutes prior to the addition of PMP to cell culture media. Perampanel addition 15 minutes follow" 11 e. glutamate exposure was sufficient to profoundly disrupt oncogenic activities of glutamate (Hg 2d).
Example!!
Dose-Dependent Anti-Cancer Activity of An Exemplar., AMPAR Antagonist, Perampanel (PMP) Potent anti-cancer efficacy of PMP compounds and other etTective AM PAR
30 antagonists is readily demonstrated using a range of animal models that are well known and wideb. accepted in the art as predictive or anti-cancer activity in humans.
One such model employs subcutaneous xenografts of tumor cells into useful study animals such as mice, to study efficacy of candidate anti-cancer drugs in reducing growth or proliferation of xenoffalted tumor cells in test versus control subjects. These studies can include monitoring of a range of indicia of therapeutic efficacy. for example to demonstrate a dose-dependent decrease (e.g.. based on average values observed in test versus control subjects) in xenografted tumor number, tumor size. tumor metastases, tissue histological and/or biochemical cancer markers (e.g.. from biopsy or necropsy-) blood cancer markers. mortality.
etc. As used herein. cancer "markers- refers to any biomolecule. such as a growth factor, genetic regulatory protein. eytokine_ hormone. receptor. etc.. whose presence.
expression, structure, level or activity is correlated with cancer incidence, severity.
progression, or another etiologic or therapeutic factor indicative of cancer growth. metabolic activity, metastasis. etc.
In useful study protocols relating to central nervous system (CNS) cancers such as glioblastoma (GUM). conventional xenograft study designs may be modified to include intracranial xenografting, to better capitulate clinical conditions of CUM
(see, for example, Ozawa et al.. 2010). In one exemplary study protocol employed herein, modified from Ozawa et al._ we employ 198G cells. a GUM cell line expressing the enzyme MGMT, which functions to repair DNA damage from temozoiomide (Mt). rendering this cell type intrinsically resistant to TMZ chemotherapy. These cells are engineered to express the bioluminescent enzyme luciferase to allow in vivo xenograft detection and quantification. A
study total of 24 mice are used, divided into four study groups of 6 members per group. The mice are anesthetized using ketamine/zylazine on a warming plate to maintain core body temperature. Once anesthetized. the scalp is swabbed with chlorohcxidine and a sagittal incision is made over the parieto-occipital bone. about lem long on the left side. The exposed skull is cleaned using a cotton swab with 3% hydrogen peroxide.
Xenograft cells are provided at a concentration of 300.000-500.000 cells in 3u1_, serum-free media, and this cell suspension is drawn into a syringe and injected at a depth of 3mm into the cortical tissue.
The injection is carried out slowly, over a period of one minute. to localize the xenografted cells focally to specific brain region and prevent dissemination of the cells into the ventricles and spinal cord. After injection., the skull is cleaned with 3% hydrogen peroxide and sterile bone wax is to the incised skull defect. The scalp is drawn over the skull and stapled closed.
Buprenorphine is optionally administered for post-operative pain relief, and recovery time is about 30 minutes.
One week after injection the study subjects are divided into 4 groups and bioluminescent monitoring of the xenografts begins. Group 1 mice receive placebo saline for the duration of the experiment. Group 2 receives 20rng/kg/day TMZ. Group 3 receives 5 or lOmg/kg/day PMP depending on what dose produces a partial effect in monotherapy experiments. Group 4 is a combination group that receives both the TMZ and PMP
treatments. Mice are bioluminescent monitored every 4 days during the study, for example using D-luciferin and an in vivo imaging system such as IVIS-200 (PerkinElmer.
Inc, Norwalk Connecticut) to measure bioluminescent photon release as a quantitative indicator of 5 tumor growth.
These and related studies will demonstrate that PMP and other anti-cancer effective AMPAR antagonists according to the teachings herein potently prevent and treat AMPAR
positive CNS cancers, including CiBM. in mammalian subjects. Particular results will demonstrate a dose-dependent reduction in overall luminescence over an effective course of 10 AMPAR antagonist treatment, correlated with reduced tumor size, reduced tumor cell number and/or reduced xenograft proliferative and/or metastatic capacity mediated by the anti-cancer AMPAR antagonist. for example PMP. PMP and other selected AMPAR
antagonist will also significantly decrease tumor cell survival, viability and proliferation, and increase correlated indicia including time to tumor doubling and tripling, as well as subject 15 survival (e.g.. by time and/or numbers of subjects). in addition to mediating significant therapeutic benefits corresponding to all other anti-cancer activity indicators described herein above In more detailed in vivo protocols. PMP will exhibit significant inhibitory activity against GBM xenograft cell viability, proliferative capacity, tumor growth and metastases at 20 concentrations of I-10uM or greater, i.e.. at plasma levels that are safe and effective for cancer chemotherapy.
In other detailed aspects. PMP will be shown to be combinatorially effective to complement anti-GUM effects of secondary anti-cancer drugs and treatments, for example temozolomide (TMZ). In certain embodiments. PMP will complement. potentiate or even 25 synergistically enhance anti-cancer activities of other drugs. for example to significantly increase overall anti-cancer effects in combination with Tmz, compared to anti-cancer effects mediated by =I'MZ, alone. In these embodiments the combinatorial use of PMP and TMZ, e_g.. at therapeutic dosage levels of PMP between about 30uM-100uMõ
provides for enhanced efficacy of TMZ and lower TMZ dosages with reduced TMZ-associated side 30 effects. an exemplary model of coordinate treatment that will be demonstrable across a range of combinations of AMPAR antagonists and secondary/adjunctive anti-cancer agents and therapies.
In related illustrative protocols the efficacy of anti-cancer AMPAR
antagonists such as PMP is demonstrated in combinatorial usage with a PRMT5 inhibitor, such as EPZ015666.
As recently reported by Braun et al (2017). high grade aliomas may be dependent on deletion of detained introns of oncogenic transcripts for sustained growth and survival. PRMT5 ensures proper splicing of these introns to become mature transcripts useful for production of various oncogenic proteins. Inhibition of PRMT5 with [PZ015666 reportedly mediates 5 oncostatic effects against GBM. In one illustrative study here, the foregoing intraeranial xenograft study design is adapted to include one individual test group of 6 mice receiving 100mg/kg/day EPZ015666. one group treated with I Omg/kg/day PMP. and a combinatorial group treated with both EPZ015666 and PMP. Bioluminescent imaging and other measures of anti-cancer efficacy will demonstrate that PMP is anti-cancer effective alone, and 10 combinatorially effective (e.g.. complementary, additive. potentiating or synergistic) in coordinate administration with EPZO I 5666.
In other illustrative protocols of the invention the efficacy of anti-cancer AMPAR
antagonists such as PMP is demonstrated in combinatorial methods with tumor treating fields. Recent studies report that electrical fields using insulated electrodes applying 15 frequencies of 200kliz can inhibit cell cycle progression in GBM cells (see. e.g., Kirson et al.
2007; and Stupp et al. 2015). In an exemplary study here. the intracraniai xenograft protocol is adapted to include one individual test group of 6 mice receiving an external insulated electrode closest to the area of the xenograk applying a 200kIlz current for the duration of the study, one group treated with 10mg/kg/day PMP. and a combinatorial group treated with 20 both therapies. Bioluminescent imaging and other measures of anti-cancer efficacy will demonstrate that PMP is anti-cancer etTective alone and combinatorially effective in coordinate administration with tumor treating fields.
In other exemplary protocols of the invention the efficacy of anti-cancer AMPAR
antagonists such as PMP is demonstrated in combinatorial therapies employing proteins that 25 interfere with telomere function of tumors. for example the TRF I
inhibitor [TP-47037. Due to rapid proliferation of most tumors. tumor cells are particularly vulnerable to DNA damage that can result in cell death. Telomeres are the caps of chromosomes made of repetitive DNA. which serve to prevent protein-coding DNA loss or damage during cell division.
Several proteins are implicated in maintaining telomeres. one of which is a protein designated 30 TRH. Recent studies report that pharmacological or genetic ablation of this TRF I reduces tumor formation and growth in animal models (see, e.g._ Bejarano et al. 2017).
In one report.
75mg/kg of ETP-47037 prevented tumor growth in mice.. In an illustrative protocol here. the intracranial xenograft protocol above is adapted to include one test group of mice receiving a therapeutic dosage of 75mg/kg of VIP-47037. one group treated with I
Orng/kg/day PMP. and a combinatorial group treated with both therapies. Bioluminescent imaging and other measures of anti-cancer efficacy VIII demonstrate that PMP is anti-cancer effective alone and combinatorially effective in coordinate administration with ETP-47037.
Additional studies are contemplated to show that combinatorial treatment with PMP provides for lower dosing of the ETP-47037 to achieve the same or greater clinical benefits, with fewer side effects (e.g.. wherein a comparable. partial anti-cancer effect as exhibited by 75mg/kg is observed in combination with PMP at reduced effective dosages of ETP-47037 of 25-50mg/kg or lower).
In another exemplary combination treatment model of the invention, the efficacy of anti-cancer AMPAR antagonists such as PMP is demonstrated in coordinate protocols with a transcription inhibitor, such as terameprocol. Terameprocol is a global transcription inhibitor that affects proliferation. apoptosis and drug resistance, currently being clinically evaluated for treatment of GBM (Grossman et al. 2012). In one representative study the intracranial xenograft study includes one test group of mice treated with 20mg/kg/day Terameprocol. one group treated with 10mg/kg/day,. PMP. and a combinatorial group treated with both therapies.
Bioluminescent imaging and other measures of anti-cancer efficacy will demonstrate that PMP is anti-cancer effective alone and combinatorially effective in coordinate administration with Terameprocol. Additional studies will show that combinatorial treatment with PMP
provides for lower dosing ofTerameprocol to achieve the same or greater clinical benefits.
with fewer side effects.
In yet additional combinatorial treatment methods of the invention, the efficacy of anti-cancer AMPAR antagonists such as PMP is demonstrated in coordinate protocols with NEK2 inhibitors. Recent studies report that EZH2 is vital for maintaining glioma stem cells, a subset of glioma cells that are responsible for chemo- and radiotherapy resistance due to their ability to regenerate new tumor cells after existing tumor cells are destroyed. NEK2 is responsible for guarding EZH2 against premature breakdown, allowing EZH2 to exert a longer and more robust oncogenic effect. Recent studies report that an inhibitor of NEK2, Cmp3a. exerts anti-cancer effects as demonstrated by prolongation of cancer survival time in mice (Wang et al. 2017). According to the modified study protocol here one group of mice receives I Oing.kg 'day Cmp3a. one group received IOm/kg/day PMP. and a combinatorial group is treated with both therapies. Bioluminescent imaging and other measures of anti-cancer efficacy will demonstrate that prvir is anti-cancer effective alone and combinatorially effeetke in coordinate administration with NEK2 inhibitors such as Cmp3a.
Additional studies will show that combinatorial treatment with PMP provides for lower dosing of NEK3 inhibitors to achieve the same or greater clinical benefits, with fewer side effects.
Example III
Anti-Cancer Activity of AMPAR Antagonists In Combination with Standard Of Care (SOC), Glioma Treatment 5 In exemplary clinical protocols of the invention, anti-cancer effective AMPAR
antagonist treatment will be combined with secondary anti-cancer therapy comprising standard of care (SOC) glioma treatments. In one illustrative example, patients are initially treated with SOC maximal safe surgical resection_ followed by an aggressive SOC
chemoradiation protocol. For the first 6 weeks of treatment, patients receive 75mg/m2/day of 10 Temozolomide (Temodar) starting one hour prior to radiation treatment.
Patients additionally receive 200cGy focal radiation per day for the First live days of the week over a 6 week timespan (30 fractions). for a total of 60Gy radiation. Radiation targets the tumor area as well as surrounding edema plus a I em margin. I month after the last radiation treatment, patients are administered I 50-200mg/m2/day, temozolomide for the first 5 days of every 15 month followed by 3 weeks rest as well as antiemetie prophylaxis treatment as needed.
Treatments are stopped ifplatelet count drops below I00.000/uL. or if there is evidence of disease progression or severe treatment-related toxicity (Grossman et at 2009). In combination with the SOC glioma treatment outlined above, patients receive 8mg peramplanel orally 1 hour prior to the first radiation session. Perampanel is further 20 administered once per day, and weekly titrated up 2 mg/day until patients receive the maximally tolerated approved dose (mTD) of 12 mg (Gidal et al, 2015) (though this range can be adjusted up or down based on patient-specific tolerance and other clinical factors determined by the managing physician). Within illustrative methods for treating GBM, patients receive the MT[) throughout an initial 6-week treatment period, during the 1 month 25 SOC rest period, and while patients are taking maintenance Temodar.
Patients are maintained on perampanel treatment as determined by the managing physician, unless disease progression or evidence of perarnplanel-related toxicity is observed_ Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-glioma therapy.
30 Example IV
Anti-Cancer Activity of AMPAR Antagonists In Combination with Levetiracetam Co-Treatment In additional clinical examples_ patients are treated concomitantly with an AMPAR
antagonist such as peramplanel and Levetiracetam (Keppra). which has been shown to augment temozolonnide efficacy (13obustue et al. 2010) and reduce aggression-related adverse events in patients taking perampanel (Kanemura et al, 2019: Kim et al. 2015).
Patients are administered perampanel as described above along with 500mg levetiracetam 1 hour prior to the first radiation session. Levetiracetam is administered twice a day. the second time being at night before bed. Within illustrative methods for treating GBM, patients receive 200-500mg levetiracetam twice a day throughout the first 6-week treatment period, during the 1 month rest period, and while patients are taking maintenance Temodar. Patients continue to receive leveliracetain and perampanel unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
Example V
Anti-Cancer Activity of AMPAR Antagonists In Combination with NMDA Receptor Antagonist Co-Treatment In other clinical protocols useful within the invention, patients are treated concomitantly with an N-methyl-D-aspartate (NMDA) receptor antagonist, such as memantine. Memantine has been reported to exert anti-cancer effects, possibly by abrogating constitutively active growth pathways in cancer (Stepulak et al, 2005: Maraka et al, 2019).
Patients receive perampanel along with 5-20mg memantine orally prior to the first radiation session. Within illustrative methods for treating GBM. perampanel and memantine are administered once a day throughout the first 6-week treatment period, during the 1 month rest period, and while patients are taking maintenance Temodar. Patients are maintained on memantine and perampanel unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
In addition to memantine. ketamine. an NMDA-antagonist used in the setting of pharrnacoresistant depression. may also be used. Ketamine is given at doses ranging from 5-500mg/day and started prior to the first radiation session. Ketamine and its active metabolite hydroxynorketamine (Zanos et al. 2016) may provide anti-cancer benefits (Malsy et al.
2015). and will be a beneficial adjunct within the methods of the invention, for example to complement standard of care + perampanel treatments.
Example VI
Anti-Cancer Activity of AMPAR Antagonists In Combination with Riluzole/Troriluzole Co-Treatment Additional clinical methods of the invention employ an AMPAR antagonist such as 5 perampanel coordinately administered with Riluzole/ troriluzole (see.
e.g.. Khan et al, 2019).
Patients receive perampanel as above in coordinate treatment with with 20-50tng Riluzole/troriluzole orally prior to the first radiation session. Within illustrative methods for treating GBM. perampanel and Rilwole/troriluzole are administered once a day throughout the first 6-week treatment period, during the I month rest period, and while patients are 10 taking maintenance Temodar. Patients are maintained on Riluzole/troriluzole and perampanel unless disease progression or evidence of drug-related toxicity is observed.
Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
Example VII
15 Anti-Cancer Activity of AMPAR Antamonists In Combination with CSF1R Inhibitors Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with a colony stimulating factor 1 receptor (CSF I R) inhibitor such as PLX3397 (plexidartinib) or PLX5562 (see. e.g., Yan et al, 2017; Butowski 20 et al. 2016). Patients are administered perampanel as above in coordinate treatment with 100-1000 mg PLX3397 orally prior to the first radiation session. Within illustrative methods for treating GUM. perarnpanel and PLX3397 are administered together or separately once a day throughout the first 6-week treatment period, during the 1 month rest period, and while patients are taking maintenance Temodar. Patients are maintained on PLX3397 and 25 perampancl unless disease progression or evidence of drug-related toxicity is observed.
Subjects treated according to this combinatorial protocol .µ ill show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy. While CSH R
inhibition is reported to provide pre-clinical anti-cancer benefitsresults (Patwardhan et al, 2014: Yan et al. 2017: Quail et al_ 2016). most pre-clinical models of different types of 30 cancer demonstrate acquired resistance throughout this treatment (Patwardhan et al.. 2014;
Quail et al. 2016). In particular. for brain cancer, it has been shown that insulin-like growth factor I (IGF I ) induces glioma rebound in CSH R inhibitor-treated mice (Quail et al, 2016).
Surprisingly. AMPA-glutanaate antagonism according to the methods described here will negate oncogenic effects of !GEL and AMPA-glutamate antagonism will complement with CSF I R inhibition to lower tumor burden in co-treated subjects. In more detailed aspects of the invention, it is noted that P'EX3397 may inhibit PDGFRB signaling in cancer 5 (Patwardhan et al. 2014). and that PDGF'RB reportedly coordinates an anti-oxidant program in cancer through NRF2 transcription (Yang et al. 2018; Nanjaiah et al. 2019).
On this basis, according to the teachings herein. PLX3397 will be beneficially combined with glutamate antagonists like memantine. within AMPAR antagonist methods of the invention, to bolster combined efficacy by suppressing an anti-oxidant program, e.g., in glioma cells.
10 Example VIII
Anti-Cancer Activity of AMPAR Antagonists In Combination with Anti-Malarial Drugs Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with one or more anti-malarial drugs such as 15 chloroquine, hydroxychloroquine. prima/wine and mefloquine (see. e.g., Johnson et al, 2015;
Liu et al, 2016: Maraka et al, 2019). In exemplary protocols. patients receive perampanel as above along with 250mg mefloquine orally prior to the first radiation session.
Within illustrative methods for treating GBM. Metloquine is administered once every two days throughout the first 6-week treatment period, during the I month rest period, and while 20 patients are taking maintenance Temodar. Patients are maintained on the anti-malarial and perampanel unless disease progression or evidence of drug-related toxicity is observed.
Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
Example VIX
25 Anti-Cancer Activity of AMPAR Antagonists In Combination with Metformin/Phenformin Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with metformin (see, e.g.. Benjamin et al.. 2016:
Maraka et al. 2019). Patients receive perampanel as above along with 500-2000mg 30 metformin orally prior to the first radiation session. In exemplary protocols for treating GBM, peranapanel and metformin are administered once a day throughout the first 6-week treatment period., during the I month rest period, and while patients are taking maintenance Temodar. Patients are maintained on the metform in and perampanel unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or 5 other conventional anti-cancer therapy.
Example X
Anti-Cancer Activity of AMPAR Antagonists In Combination with PD-I Inhibitor Treatment Additional clinical methods of the invention employ an AMPAR antagonist such as 10 perampanel coordinate!) administered with anti-cancer biologics including programmed cell death protein I (PD-1) inhibitors, such as pembroliitimab or nivolumab (see, e.g., Nghiem et al. 2016: Motzer et al. 2015). Resistance to PD- I antagonism has been attributed to TNF-a production in the tumor microenvironment (Neubert et al. 2018). Since Ampa-glutamate antagonism has been shown to reduce TNF-a secretion in a model of intraventricular 15 hemorrhage (Dohare et al. 2016). AMPAR antagonist treatment according to the invention will augment the efficacy of PD- I inhibitors. In exemplary protocols, patients are administered perampanel as above, in conjunction with I-3mg/kg pembrolizumabinivolumab intravenously prior to the first radiation session. Within illustrative methods for treating GBM. patients then receive pembrolizumabinivolumab every 2 weeks throughout the first 6-20 week treatment period. during the 1 month rest period, and while patients are taking maintenance Temodar. Treatment is continued thusly unless disease progression or evidence of drug-related toxicity appears. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
25 Example XI
Anti-Cancer Activity of AMPAR Antagonists In Combination with PD- I Inhibitor + CSF I R Inhibitor Treatment Within more detailed examples. AMPAR antagonists such as perampanel are coordinately administered with PD- I inhibitors, and also with CSF I R
inhibitors. Notably, 30 while PD-I inhibitors reportedl) exhibit robust efficacy in some patients, they appear to have little to no therapeutic effects in other patients. Recently. it has been suggested that CSF I
and TN F-a secretion by tumor cells may stanch the efficacy of' PD-I therapy (Neubert et al, 2018). As disclosed herein, patients be treated with a combination of AMPAR
antagonists PD-1 inhibitors and CSF I R inhibitors (e.g.. with perampancl, pembrolizumab.
and PLX3397) will benefit by reduced CSF1 signaling in the tumor mieroenvironment, combined with 5 ampa-glutannate antagonist repression of `INF signaling (see, e.g..
Dohare et al, 2016).
negating PD-1 inhibitor resistance to yield enhanced clinical benefits over SOC or other conventional anti-cancer therapy.
,Exaniple XII
Anti-Cancer Activity of AMPAR Antagonists In Combination with 10 Clemastine Fumarate Co-Treatment Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with clemastine fumarate (see, e.g., Diibbeling et al, 2013: Le Joncour et al. 2019). Patients are administered perm-vane' as above along with 0.5-2.68mg clemastine fumarate orally prior to the first radiation session. In illustrative protocols 15 for treating GBM, perampanel and clemastine are taken once a day throughout the first 6-week treatment period_ during the I month rest period, and while patients are taking maintenance Temodar. Patients are maintained on the clemastine fumarate and perampanel unless disease progression or evidence of drug-related toxicity is observed.
Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits 20 over SOC or other conventional anti-cancer therapy.
Example XIII
Anti-Cancer Activity of AMPAR Antagonists In Combination with SSRI Co-Treatment Additional clinical methods of the invention employ an AMPAR antagonist such as 25 perampanel coordinately administered with one or more selective serotonin reuptake inhibitors (SSR1s) (see. e.g.. Sun et al. 2018: Huang et al. 2011: I,in et al.
2010: Liu et al, 2015: Yuan et al. 2018: Raabe & Gentile. 2008). In exemplary protocols for treating CiBM, patients are administered perampanel along with the SSRI(s) orally prior to the first radiation session, then once a day throughout the first 6-week treatment period, during the 1 month rest 30 period, and while patients are taking maintenance Temodar. Patients are maintained on the SSRI and perampanel unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
Example XIV
Anti-Cancer Activity of AMPAR Antagonists In Combination with 5 TCA Co-Treatment Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with one or more tricyclic antidepressants (TCAs) (see, e.g._ Jahchan et al, 2013; Jeon et al. 2011: Raabe & Gentile, 2008;
Reynolds & Miller, 1988: Semagor et al_ 1989: Stoll et al. 2007). Patients receive perampanel along with the 10 TCA(s) orally prior to the first radiation session. In exemplary protocols for treating GBM, the perampanel and TCA are then each administered once a day throughout the first 6-week treatment period, during the I month rest period_ and while patients are taking maintenance Temodar. Patients are maintained on the TCA and perampanel unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this 15 combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
Example XV
Anti-Cancer Activity of AMPAR Antagonists In Combination with Ampakine Co-Treatment 20 Additional clinical methods of the invention employ an AMPAR
antagonist such as perampanel coordinately administered with one or more positive allosteric AMPA
receptor modulators (Ampakines). In exemplary protocols. patients are administered perampanenl in combination with one or more ampakines. such as 2.3.6a.7.8.9-hexahydro-1 I H-l.4-dioxino[2.3-glpyrrolo[2.1-b][ 1.3Jbenzoxa7ine-I 1-one (-CX614-) (see. e.g., Radin et al.
25 2018). Though ampakines are thought to augment AMPA-mediated currents in neurons, they have also been reported to induce AMPA receptor desensitization and down regulation via endocytosis and degradation after prolonged treatment (Jourdi et al_ 2005), whereby they may serve as functional antagonists. Within illustrative methods for treating GBM, patients are administered perampanel along with CX614 or another amplakine orally prior to the first 30 radiation session. then once a day throughout the first 6-week treatment period, during the 1 month rest period, and while patients are taking maintenance Temodar. Patients are maintained on the ampakine(s) and perampanel unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
Example XVI
Anti-Cancer Activity of AMPAR Antagonists In Combination with Cannabinoid Co-Treatment Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with one or more cannabinoids, for example tetrahydroeannabinol (-111C) and/or cannabidiol (CBD) (see. e.g.. Scott et al, 2014; Mareu et al. 2010; Shrisastava et al. 2011). In exemplary protocols for treating GBM, patients are administered perampanel along with I 00-600mg CID and 1-100ing T-IC prior to the first radiation session. then once a day throughout the first 6-week treatment period, during the 1 month rest period, and while patients are taking maintenance Ternodar.
Patients are maintained on the cannabinoid and perampanel therapy unless disease progression or evidence of drug-related toxicit) is observed. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy. For treatment of GBM. cannabinoids have been reported to potent effects on glioma stem cells (Lepez-Valero et al_ 2018). Considering that AMPA
receptors are overexpressed on glionia stem cells (Oh et al. 2012). the combinatorial treatment methods and compositions described here w ill sensitize resistant tumor cells to the DNA-damaging effects of Ternodar and radiation therapy (McLendon et al_ 2006;
Chen et al, 2012) and thereby enhance clinical benefits. Further. cannabinoids reportedly exert oncolytic effects through induction of harmful reactive oxygen species (Shrivastava et al, 2011;
Nanjaiah et al, 2019). whereby the methods and compositions of the invention combining cannabinoids with glutamate antagonists will negate antioxidant defenses in cancer cells and enhance clinical benefits. particularly in elioma patients.
Example XVI
.Anti-Cancer Activitv of AMPAR Antagonists In Combination with Distil firam Co-Treatment Yet additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with disulfirarn (see, e.g., Lun et al, 2016; Triscon et al, 2012). Disulfiram targets cancer stem cells and reportedly inhibits MGMT to boost efficacy of Temodar (Paranjpe et al. 2014). Within the methods of the invention, both 5 disulfiram and perampanel augment Temodar's efficacy and refine targeting of cancer cells, yielding surprisingly enhanced benefits for treating SOC treatment-resistant cancers. Within exemplary methods for treating GBM. patients are administered perampanel along with 50-500mu disulfiram orally prior to the first radiation session, then once daily throughout the first 6-week treatment period. during the 1 month rest period, and while patients are taking 10 maintenance Temodar. Patients are maintained on the perampanel and disulfiram unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
The instant description and examples are provided lor illustration, and those skilled in 15 the art will realize that the invention extends to additional embodiments and aspects following the teachings herein, and is therefore not limited except as by the appended claims.
References 1. Grossman, S. A., Ye, X., Chamberlain. M., Mikkelsen, T.. Batchelor, T., Desideri, S., ... Fine, H. A. (2009). Talampanel with standard radiation and temozolomide in patients with newly diagnosed glioblastorna: A multicenter phase 11 trial.
Journal of 5 Clinical Oncology, 27(25), 4155-416 I .
2. Gidal. B. E., Laurenza. µA.. Hussein. Z., Yang, H., Fain, It, Edelstein, J., ... Ferry, J.
(2015). Perampanel efficacy and tolerability with enzyme-inducing AEDs in patients with epilepsy. Neurology, 84(19), 1972-1980.
3 Bobustuc, G. C., Baker, C. H.. Limaye. A., Jenkins, W. D., Pearl, G., Avgeropoulos.
10 N. G., & Konduri. S. D. (2010). Levetiracetam enhances p53-mediated MGMT
inhibition and sensitizes glioblastoma cells to temozolomide. Neuro-Oncology, 12(9), 917-927.
4 Kanemura, H., Sano, F., & Aihara. M. (2019).
Usefulness of perampanel with concomitant levetiracetam for patients with drug-resistant epilepsy. European Journal 15 q-Paediatric- Neurology, 23(1). 197-203.
5. Kim, Y._ Kim, it Jot), J., Han. J. H.. Kim, Y.
J., Kim. I. A._ . Kim, C. (2015).
Survival benefit of levetiracetam in patients treated with concomitant chemoradiotherapy and adjuvant chemotherapy with temozolomide for glioblastoma multiforme. Cancer. 121(17). 2926-2932.
20 6 Stepulak, A.. Sifringer, M. Rzeski. W., Endesfelder, S.. Gratopp, A., Pohl, E. E, lkonomidou. C. (2005). NMDA antagonist inhibits the extracellular signal-regulated kinase pathway and suppresses cancer growth. Proceedings of the National Academy .Sc.lences the United States of America, 102(43), I 5605- l 5610.
7 Maraka, S., Groves, M. D., Mammoser. A. G., Melguizo-Gavilanes, 1., Conrad, C. A., 25 Tremont-Lukats, I. W., Penas-Prado, M. (2019). Phase 1 lead-in to a phase 2 factorial study of temozolomide plus memantine, mefloquine, and metformin as postradiation adjuvant therapy for newly diagnosed glioblastoma. Cancer, 125(3), 424-433.
8 Zanos, P., Moaddel. It. Morris. P. J., Georgiou, P.. Fischell, J., Elmer, G. 1., .
30 Gould, T. D. (2016). NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature, 533(7604), 481-486.
9 Malsy, M.. Gebhardt, K.. (lather, M., Wiese. C.. Graf, B.. & Bundscherer, A.
(2015).
Effects of ketamine. s-ketamine. and MK 801 on proliferation, apoptosis. and necrosis in pancreatic cancer cells. BAK' Anesthesiologv, 15(1). I 11-118.
35 to Khan, A. J., LaCava, S., Mehta, M., Schiff. D., Thandoni. A., Jhawar, S., ... Chen, S.
(2019). The glutamate release inhibitor riluzole increases DNA damage and enhances cvtotoxicity in human glioma cells_ in vitro and in vivo. Oncotarget, /0(29), 2834.
it Van, D., Kovyal, J., Akkari_ L., Schuhmacher_ A. J., Huse. J. T.. West, B.
L., & Joyce, 40 J. A. (2017). Inhibition of colony stimulating factor-1 receptor abrogates microenvironment-mediated therapeutic resistance in gliomas. Oncogene, 36(43).
6049-6058.
12 Butowski, N., Colman, H., De Groot, J. F.. Omuro, A. M., Nayak, L., Wen, P.
Y., . .
Prados. M. (2016). Orally administered colony stimulating factor 1 receptor inhibitor 45 PLX3397 in recurrent glioblastoma: An ivy foundation early phase clinical trials consortium phase It study. Nettro-Oncoloff, /8(4). 557-564.
13. Patwardhan. P. P., Surriga, 0.. Beckman, M. J., de Stanehina. E., Dematteo, R. P., Tap. W. D.. & Schwartz. G. K. (2014). Sustained inhibition of receptor tyrosine kinases and macrophage depletion by PLX3397 and rapamycin as a potential new approach for the treatment of MPNSTs. Clinical Cancer Research 20(12), 3 I 46-3158.
14. Yan, D., Kowal, J., Akkari, L., Schuhmacher, A. J., Huse, J. T., West, B.
L., & Joyce, J. A. (2017). Inhibition of colony stimulating factor-I receptor abrogates 5 microenvironment-mediated therapeutic resistance in gliomas.
Oncogene, 36(43), 6049-6058.
15. Quail, D. F., Bowman, R. L., Akkari, L., Quick, M. L., Schuhmacher, A. J., Huse, J.
T.,.. . Joyce, J. A. (2016). The tumor microenvironment underlies acquired resistance to CSF-I R inhibition in gliomas. Science. 352(6288).
10 16. Stepulak, A., Sifringer, M., Rzeski, W., Brocke, K., Gratopp, A., Pohl, E. F.....
lkonomidou, C. (2007). AMPA antagonists inhibit the extracellular signal regulated kinase pathway and suppress lung cancer growth. Cancer Biology & Therapy, 6(12), 1908.
17 Yang, Z.. Yang. Y., Deng. Y., Chen. Y., Chen. X., Zhang. L..... Liu, B.
(2018).
15 Inhibition of PDGFR by CP-67345I induces apoptosis and increases cisplatin cytotoxicity in NSCI.0 cells via inhibiting the Nr12-mediated defense mechanism. 7in/eulogy Letters, 295, 88-98.
ia Nanjaiah, N. D., Ramaswamy, P., Goswarni. K., Hurmath Fathima, K., &
Borkotokey, M. (2019). Survival of glioblastoma cells in response to endogenous and 20 exogenous oxidative challenges: Possible implication of NMDA
receptor mediated regulation of redox homeostasis. Cell Biology International, 11193. 1-10.
is. Johnson, C. E., Hunt, D. K., Wiltshire, M., Herbert, T. P., Sampson, J.
R., Errington, R. J.,.,. . Tee, A. R. (2015). Endoplasmic reticulum stress and cell death in mTORC1-overactive cells is induced by nelfinavir and enhanced by chloroquine.
Molecular 25 Oncofoff, 9(3), 675-688.
20 Liu, Y., Chen. S... Xue. R.. Zhao, J.. & Di. M. (2016). Mefloquine effectively targets gastric cancer cells through phosphatase-dependent inhibition of P13K/Akt/inTOR
signaling pathway. Biochemical and Biophysical Research Communications, 470(2), 350-355.
30 21 Benjamin, D., Colombi, M.. Hindupur, S. K.. Betz. C.. Lane* H. A., EI-Shemerly, M.
Y. M..... Hall, M. N. (2016). Syrosingopine sensitizes cancer cells to killing by metformin. Science Advances. 2(12), el60 I 756-el 601 756.
22 Nghiem. P. T., Bhatia. S., Lipson. E. J.. Kudchadkar, R. It.. Miller, N.
J.., Annamalai, L..... Cheever, M. A. (2016). PD-1 blockade with pembrolizunaab in advanced 35 merkel-cell carcinoma. The New England Journal of Medicine, 374(26), 2542-2552.
23. Motzer, R. J., Escudier, B., McDermott. D. F., George, S., Hammers, H. J., Srinivas, S., .. CheckMate 025 Investigators. (2015). Nivolumab versus everolimus in advanced renal-cell carcinoma. The Neu, England Journal of Medicine. 373(19), 1803-1813.
40 24 Neubert. N. J., Schmittnaegel, M., Bordry, N., Nassiri, S., Wald, N., Martignier, C.,..
. Speiser. D. E. (2018). T cell-induced CSF I promotes melanoma resistance to PDI
blockade. Science Translational Medicine. 10(436), 1-14.
25 Dohare. P., Zia. M. T.. Ahmed. E.. Ahmed. A.. Yadala. V.. Schober, A. L., .
.
Ballabh, P. (2016). AMPA-kainate receptor inhibition promotes neurologic recovery 45 in premature rabbits with intraventricular hemorrhage...!
Neuravci. 36(11), 3363-3377.
26 DObbeling. U.. Waeckerle-Men. Y._ Zabel, F.. Graf. N., Ktindig, T. M., ez.
Johansen, P. (2013). The antihistamines clemastine and desloratadine inhibit STAT3 and e-myc activities and induce apoptosis in cutaneous T-cell lymphoma cell lines.
Evperimental 50 Dennatology, 22(2),, 119.
2T Le Joncour, V., Filppu, P., Hyvonen, M., Holopainen, M., Turunen, S. P., Sihto, H,..
. Laakkonen. P. (2019). Vulnerability of invasive glioblastoma cells to lysosorrial membrane destabilization. EMBO Molecular Medicine, 1/(6), e9034.
28 Sun. D., Zhu, L., Zhao, Y., Jiang, Y.. Chen, L., Yu, Y., & Ouyang, L.
(2018).
5 Fluoxetine induces autophagic cell death via eET2K-AMPK-mTOR-ULK
complex axis in triple negative breast cancer_ Cell Prolijeration, 5/(2). e 12402.
29. Huang, J., Chang, EL, Chou, C., Shu, S., Kuo, C., Tsai, J., Jan, C. (2011). The mechanism of sertraline-induced [Ca2-1-li rise in human PC3 prostate cancer cells:
Sertraline and human prostate cancer cells. Basic & Clinical Pharmacology &
10 Toxicology. 109(2), 103-110.
30 Lin. C., Robert_ F., Sukarieh, R., Michnick, S.. & Pelletier, J. (2010).
The antidepressant sertraline inhibits translation initiation by curtailing mammalian target of rapamycin signaling. Cancer Research, 70(8), 3199-3208.
31. Yuan, I., Honig, C.. Chen, V. C., Chen, C.. Chen, L., Hsu, T., & Tzang, B.
(2018).
15 Escitalopram oxalate inhibits proliferation and migration and induces apoptosis in non-small cell lung cancer cells. Oncology Letters; 15(3), 3376-3382.
32 Sun, D., Zhu. L., Zhao, Y., Jiang, Y., Chen, L., Yu, Y., & Ouyang, L.
(2018).
Fluoxetine induces autophagic cell death via eET2K-AMPK-mTOR-ULK complex axis in triple negative breast cancer. Cell Praliferation, 51(2), e I 2402.
20 33 Liu, K., Yang, S., Lin. Y., Lin, J.. Lee. Y., Wang, J.... . Shen, S. (2015). Fluoxetine, an antidepressant, suppresses glioblastoma by evoking AM PAR-mediated calcium-dependent apoptosis. Oncotarget, 6(7), 5088-5101.
34. Raabe, R.. & Gentile, L. (2008). Antidepressant interactions with the NMDA
NR1-lb subunit. Journal of Biophysics, 2008. 474205-8.
25 35. Jahchan, N. S., Dudley. J. -1`., Mazur, P. K., Flores. N., Yang, D., Palmerton, A., Sage, J. (2013). A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer and other neuroendocrine tumors. Cancer Discovery, 3(12), 1364-1377.
36. icon, S... Kim, Y. S., Kim. Y., Kim, S. H., Lim, Y., Lee, Y. H.. & Shin, S. Y. (2011).
30 The tricyclic antidepressant imipramine induces autophagic cell death in 1.1-87MG
glioma cells. Biochemical and Biophysical Research Communications, 4/3(2), 311-3 I 7.
37. Reynolds, 1. J., & Miller, R. J. (1988). Tricyclic antidepressants block N-methyl-D-aspartate receptors: Similarities to the action of zinc. British Journal of 35 Pharmacology, 95(1). 95-102.
38 Sernagor, E., Kuhn, D., Vyklicky, L.. & Mayer, M. L. (1989). Open channel block of NMDA receptor responses evoked by tricyclic antidepressants. Neuron, 2(3), 1227.
39. Stoll, L., Seguin, S., & Gentile, L. (2007). Tricyclic antidepressants, but not the 40 selective serotonin reuptake inhibitor fluoxetine, bind to the SI
S2 domain of AMPA
receptors. Archives of Biochemistry and Biophysics, 458(2). 213-219.
40 Raclin. D. P.. Purcell. R.. & Lippa. A. S. (2018). Oncolytic properties of ampakines in vitro. Anticancer Research. 38(1). 265-269.
41 Jourdi, FL_ Lu, X.. Yanagihara. T., Latitcrborn. J. C.. Hi, X.. Gall, C.
M., & BaucIry, 45 M. (2005). Prolonged positive modulation of alpha-amino-3-hydroxy-5-methy1-4-isoxazolepropionic acid (AMPA) receptors induces calpain-mediated PSD-95/DIWZO-1 protein degradation and AMPA receptor down-regulation in cultured hippocampal slices. The Journal of Pharmacology and Experimental Therapeutics, 314(1), 16.
42 Scott, K. A., Dalgleish, A. G., & Liu, W. M. (2014). The combination of eannabidiol and A9-tetrahydrocannabinol enhances the anticancer effects of radiation in an orthotopic murine glioma model. Molecular Cancer Therapeutics, 13(12), 2955-2967.
43. Marcus J. P._ Christian. R. T.. Lau, D.. Zielinski. A. J., Horowitz, M.
P., 5 McAllister. S. D. (2010). Cannabidiol enhances the inhibitory effects of A9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival. Molecular Cancer Therapeutics, 9(1), 180.
44. Shrivastava. A., Kuzontkoski, P. M., Grooptnan, J. E., & Prasad, A.
(2011).
Cannabidiol induces programmed cell death in breast cancer cells by coordinating the 10 cross-talk between apoptosis and autophagy. Molecular Cancer Therapeutics, 10(7), 1161-1172.
45. LOpez-Valero, I., Saiz-Ladera. C, Torres, S., Hernandez-Tiedra, S., Garcia-Taboada, E., Rodriguez-Fornes.
. Velasco, G. (2018). Targeting glioma initiating cells with A combined therapy of eannabinoids and temozolomide.Biochemical 1_5 Pharmacology, 157, 266-274.
46. Oh, M. C., Kim, J. M., Safaee, M., Kaur. a, Sun, M. Z.. Kaur_ R., Parsa, A. T.
(2012). Overexpression olcalcium-permeable glutamate receptors in glioblastoma derived brain tumor initiating cells. PIUS One, 7(10). e47846-e47846.
47. McLendon, R. E., Hjelmeland, A. B., Dewhirst, M. W., Shi, Q., Rich, J. N., Wu. Q.,.
20 Hao. Y. (2006). Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature, 444(712(1), 756-760.
48 Chen, J., Li_ Y., Yu, T., McKay, R. M., Burns, D. K., Kernie, S. G., &
Parada, L. F.
(2012). A restricted cell population propagates glioblastoma growth after chemotherapy. Nature, 488(7412), 522-526.
25 49 Lun, X., Wells, J. C., Grinshtein, N., King, J. C., Mao, X., Dang, N., ... Senger, D. L.
(2016). Disulftram when combined with copper enhances the therapeutic effects of temozolomide for the treatment of glioblastoma. Clinical Cancer Research, 22(15), 3860-3875.
50 Triscott, J., Lee.. C., Hu. IC Fotovati, A.. Berns, R., Pambid_ M., ...
Dunn, S. E.
30 (2012). Disulfiram. a drug widely used to control alcoholism, suppresses the self-renewal of glioblastoma and over-rides resistance to temozolomide. maim-gel. 3(10). 1112-1123.
51 Paranjpe, A., Zhang, R., Ali-Osman, F., Bobustuc. G. C., & Srivenugopal, K.
S.
(2014). Disulfiram is a direct and potent inhibitor of human 06-methylguanine-DNA
35 methyltransferase (MGMT) in brain tumor cells and mouse brain and markedly increases the alkylating DNA damage. Carcinogenesis, 35(3), 692-702.
52 Merrier. A.. Sattliunaite. D.. Michalski_ C. W.. Erkan. M., De Oliveira.
T., Abiatari. 1..
. KleelT, J. (2011). Glutamate increases pancreatic cancer cell invasion and migration via AMPA receptor activation and Kras-MAPK signaling. in/i Cancer, 40 129(10). 2349-2359.
53 iShiliChi. S.. Tsuzuki, K.. Yoshida, Y._ Yamada. N... Magimura, N., Okado, H....
07awa, S. (2002). Blockage of Ca(2+)-permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells. Nat Med, 8(9), 978.
Ishiuchi, S.. Yoshida. Y.. Sugawara, K.. Aihara, M., Ohtani, T., Watanabe, T., . .
Ozawa. S. (2007). Ca2+-permeable AMPA receptors regulate growth of human glioblastoma via Akt activation. J Neurosci. 27(30), 7987-8001.
55. von Roetneling, C. A., Radisky, D. C., Marlow. L. A.. Cooper, S. J., Grebe, S. K., 5 Anastasiadis, P. Copland. J. A. (2014). Neuronal pentraxin 2 supports clear cell renal cell carcinoma by activating the AMPA-selective glutamate receptor-4.
Cancer Res, 74(17). 4796-4810.
5. Prasad, G., Sottero. T.. Yang. X.., Mueller. S.. James. C. D.. Weiss. W.
A., .. . Haas-Kogan. D. A. (2011). Inhibition of P13K/mTOR pathways in glioblastoma and 10 implications for combination theram, \ ith ternozolomide. Neut.() Oncol. /3(4). 384-_392.
57 Piao. V.. Lu. L.. & de Groot. J. (2009). ANIPA receptors promote perivascular glioma invasion via beta I inteurin-dependent adhesion to the extracellular matrix.
Neuro Oncol, 11(3).260-273.
15 58 Hu. H._ Takano. N.. Xiang. L.. Gilkes. D. M.. Luc,.
Semenza. G. L. (2014).
Hypoxia-inducible factors enhance glutamate signaling in cancer cells.
Oncotarget, 5(19). 8853-8868.
59. Takano. T., Lin, J. H., Areuino. G., Gaff. Q.. Yana, J., & Nedergaard, M.
(2001).
Glutamate release promotes growth of malignant tzliomas. Na! Med, 7(9), 1010-1015.
20 so Rzeski. W., Turski. L. & lkonomidou. C. (2001). Glutamate antagonists limit tumor growth. Prot- Nail Acad Sci US A. 98(11). 6372-6377.
61 Chen. C.. Maw In. Hell_ J. W._ JEL Rogawski. M. A. (2014). Perampanel inhibition of AMPA receptor currents in cultured hippocampal neurons. PloS One, 9(9), e108021.
62 Patsalos. PN. (2015). The clinical pharmacology profile of the new antiepileptie drug 25 perampanel: A novel noncompetitive AMPA receptor antagonist.
Epilepsia. 56(1).
12-27.
63 Biancur. D. E.. Paulo. J. A... Malachowska. B.. Maria Quiles Del Rey.
Sousa, C. M., Wang. X..... Kimmelman. A. C. (2017). Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism. Nature 30 Communications, N. 15965.
Johansen, P. (2013). The antihistamines clemastine and desloratadine inhibit STAT3 and e-myc activities and induce apoptosis in cutaneous T-cell lymphoma cell lines.
Evperimental 50 Dennatology, 22(2),, 119.
2T Le Joncour, V., Filppu, P., Hyvonen, M., Holopainen, M., Turunen, S. P., Sihto, H,..
. Laakkonen. P. (2019). Vulnerability of invasive glioblastoma cells to lysosorrial membrane destabilization. EMBO Molecular Medicine, 1/(6), e9034.
28 Sun. D., Zhu, L., Zhao, Y., Jiang, Y.. Chen, L., Yu, Y., & Ouyang, L.
(2018).
5 Fluoxetine induces autophagic cell death via eET2K-AMPK-mTOR-ULK
complex axis in triple negative breast cancer_ Cell Prolijeration, 5/(2). e 12402.
29. Huang, J., Chang, EL, Chou, C., Shu, S., Kuo, C., Tsai, J., Jan, C. (2011). The mechanism of sertraline-induced [Ca2-1-li rise in human PC3 prostate cancer cells:
Sertraline and human prostate cancer cells. Basic & Clinical Pharmacology &
10 Toxicology. 109(2), 103-110.
30 Lin. C., Robert_ F., Sukarieh, R., Michnick, S.. & Pelletier, J. (2010).
The antidepressant sertraline inhibits translation initiation by curtailing mammalian target of rapamycin signaling. Cancer Research, 70(8), 3199-3208.
31. Yuan, I., Honig, C.. Chen, V. C., Chen, C.. Chen, L., Hsu, T., & Tzang, B.
(2018).
15 Escitalopram oxalate inhibits proliferation and migration and induces apoptosis in non-small cell lung cancer cells. Oncology Letters; 15(3), 3376-3382.
32 Sun, D., Zhu. L., Zhao, Y., Jiang, Y., Chen, L., Yu, Y., & Ouyang, L.
(2018).
Fluoxetine induces autophagic cell death via eET2K-AMPK-mTOR-ULK complex axis in triple negative breast cancer. Cell Praliferation, 51(2), e I 2402.
20 33 Liu, K., Yang, S., Lin. Y., Lin, J.. Lee. Y., Wang, J.... . Shen, S. (2015). Fluoxetine, an antidepressant, suppresses glioblastoma by evoking AM PAR-mediated calcium-dependent apoptosis. Oncotarget, 6(7), 5088-5101.
34. Raabe, R.. & Gentile, L. (2008). Antidepressant interactions with the NMDA
NR1-lb subunit. Journal of Biophysics, 2008. 474205-8.
25 35. Jahchan, N. S., Dudley. J. -1`., Mazur, P. K., Flores. N., Yang, D., Palmerton, A., Sage, J. (2013). A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer and other neuroendocrine tumors. Cancer Discovery, 3(12), 1364-1377.
36. icon, S... Kim, Y. S., Kim. Y., Kim, S. H., Lim, Y., Lee, Y. H.. & Shin, S. Y. (2011).
30 The tricyclic antidepressant imipramine induces autophagic cell death in 1.1-87MG
glioma cells. Biochemical and Biophysical Research Communications, 4/3(2), 311-3 I 7.
37. Reynolds, 1. J., & Miller, R. J. (1988). Tricyclic antidepressants block N-methyl-D-aspartate receptors: Similarities to the action of zinc. British Journal of 35 Pharmacology, 95(1). 95-102.
38 Sernagor, E., Kuhn, D., Vyklicky, L.. & Mayer, M. L. (1989). Open channel block of NMDA receptor responses evoked by tricyclic antidepressants. Neuron, 2(3), 1227.
39. Stoll, L., Seguin, S., & Gentile, L. (2007). Tricyclic antidepressants, but not the 40 selective serotonin reuptake inhibitor fluoxetine, bind to the SI
S2 domain of AMPA
receptors. Archives of Biochemistry and Biophysics, 458(2). 213-219.
40 Raclin. D. P.. Purcell. R.. & Lippa. A. S. (2018). Oncolytic properties of ampakines in vitro. Anticancer Research. 38(1). 265-269.
41 Jourdi, FL_ Lu, X.. Yanagihara. T., Latitcrborn. J. C.. Hi, X.. Gall, C.
M., & BaucIry, 45 M. (2005). Prolonged positive modulation of alpha-amino-3-hydroxy-5-methy1-4-isoxazolepropionic acid (AMPA) receptors induces calpain-mediated PSD-95/DIWZO-1 protein degradation and AMPA receptor down-regulation in cultured hippocampal slices. The Journal of Pharmacology and Experimental Therapeutics, 314(1), 16.
42 Scott, K. A., Dalgleish, A. G., & Liu, W. M. (2014). The combination of eannabidiol and A9-tetrahydrocannabinol enhances the anticancer effects of radiation in an orthotopic murine glioma model. Molecular Cancer Therapeutics, 13(12), 2955-2967.
43. Marcus J. P._ Christian. R. T.. Lau, D.. Zielinski. A. J., Horowitz, M.
P., 5 McAllister. S. D. (2010). Cannabidiol enhances the inhibitory effects of A9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival. Molecular Cancer Therapeutics, 9(1), 180.
44. Shrivastava. A., Kuzontkoski, P. M., Grooptnan, J. E., & Prasad, A.
(2011).
Cannabidiol induces programmed cell death in breast cancer cells by coordinating the 10 cross-talk between apoptosis and autophagy. Molecular Cancer Therapeutics, 10(7), 1161-1172.
45. LOpez-Valero, I., Saiz-Ladera. C, Torres, S., Hernandez-Tiedra, S., Garcia-Taboada, E., Rodriguez-Fornes.
. Velasco, G. (2018). Targeting glioma initiating cells with A combined therapy of eannabinoids and temozolomide.Biochemical 1_5 Pharmacology, 157, 266-274.
46. Oh, M. C., Kim, J. M., Safaee, M., Kaur. a, Sun, M. Z.. Kaur_ R., Parsa, A. T.
(2012). Overexpression olcalcium-permeable glutamate receptors in glioblastoma derived brain tumor initiating cells. PIUS One, 7(10). e47846-e47846.
47. McLendon, R. E., Hjelmeland, A. B., Dewhirst, M. W., Shi, Q., Rich, J. N., Wu. Q.,.
20 Hao. Y. (2006). Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature, 444(712(1), 756-760.
48 Chen, J., Li_ Y., Yu, T., McKay, R. M., Burns, D. K., Kernie, S. G., &
Parada, L. F.
(2012). A restricted cell population propagates glioblastoma growth after chemotherapy. Nature, 488(7412), 522-526.
25 49 Lun, X., Wells, J. C., Grinshtein, N., King, J. C., Mao, X., Dang, N., ... Senger, D. L.
(2016). Disulftram when combined with copper enhances the therapeutic effects of temozolomide for the treatment of glioblastoma. Clinical Cancer Research, 22(15), 3860-3875.
50 Triscott, J., Lee.. C., Hu. IC Fotovati, A.. Berns, R., Pambid_ M., ...
Dunn, S. E.
30 (2012). Disulfiram. a drug widely used to control alcoholism, suppresses the self-renewal of glioblastoma and over-rides resistance to temozolomide. maim-gel. 3(10). 1112-1123.
51 Paranjpe, A., Zhang, R., Ali-Osman, F., Bobustuc. G. C., & Srivenugopal, K.
S.
(2014). Disulfiram is a direct and potent inhibitor of human 06-methylguanine-DNA
35 methyltransferase (MGMT) in brain tumor cells and mouse brain and markedly increases the alkylating DNA damage. Carcinogenesis, 35(3), 692-702.
52 Merrier. A.. Sattliunaite. D.. Michalski_ C. W.. Erkan. M., De Oliveira.
T., Abiatari. 1..
. KleelT, J. (2011). Glutamate increases pancreatic cancer cell invasion and migration via AMPA receptor activation and Kras-MAPK signaling. in/i Cancer, 40 129(10). 2349-2359.
53 iShiliChi. S.. Tsuzuki, K.. Yoshida, Y._ Yamada. N... Magimura, N., Okado, H....
07awa, S. (2002). Blockage of Ca(2+)-permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells. Nat Med, 8(9), 978.
Ishiuchi, S.. Yoshida. Y.. Sugawara, K.. Aihara, M., Ohtani, T., Watanabe, T., . .
Ozawa. S. (2007). Ca2+-permeable AMPA receptors regulate growth of human glioblastoma via Akt activation. J Neurosci. 27(30), 7987-8001.
55. von Roetneling, C. A., Radisky, D. C., Marlow. L. A.. Cooper, S. J., Grebe, S. K., 5 Anastasiadis, P. Copland. J. A. (2014). Neuronal pentraxin 2 supports clear cell renal cell carcinoma by activating the AMPA-selective glutamate receptor-4.
Cancer Res, 74(17). 4796-4810.
5. Prasad, G., Sottero. T.. Yang. X.., Mueller. S.. James. C. D.. Weiss. W.
A., .. . Haas-Kogan. D. A. (2011). Inhibition of P13K/mTOR pathways in glioblastoma and 10 implications for combination theram, \ ith ternozolomide. Neut.() Oncol. /3(4). 384-_392.
57 Piao. V.. Lu. L.. & de Groot. J. (2009). ANIPA receptors promote perivascular glioma invasion via beta I inteurin-dependent adhesion to the extracellular matrix.
Neuro Oncol, 11(3).260-273.
15 58 Hu. H._ Takano. N.. Xiang. L.. Gilkes. D. M.. Luc,.
Semenza. G. L. (2014).
Hypoxia-inducible factors enhance glutamate signaling in cancer cells.
Oncotarget, 5(19). 8853-8868.
59. Takano. T., Lin, J. H., Areuino. G., Gaff. Q.. Yana, J., & Nedergaard, M.
(2001).
Glutamate release promotes growth of malignant tzliomas. Na! Med, 7(9), 1010-1015.
20 so Rzeski. W., Turski. L. & lkonomidou. C. (2001). Glutamate antagonists limit tumor growth. Prot- Nail Acad Sci US A. 98(11). 6372-6377.
61 Chen. C.. Maw In. Hell_ J. W._ JEL Rogawski. M. A. (2014). Perampanel inhibition of AMPA receptor currents in cultured hippocampal neurons. PloS One, 9(9), e108021.
62 Patsalos. PN. (2015). The clinical pharmacology profile of the new antiepileptie drug 25 perampanel: A novel noncompetitive AMPA receptor antagonist.
Epilepsia. 56(1).
12-27.
63 Biancur. D. E.. Paulo. J. A... Malachowska. B.. Maria Quiles Del Rey.
Sousa, C. M., Wang. X..... Kimmelman. A. C. (2017). Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism. Nature 30 Communications, N. 15965.
Claims (26)
1. A method for treating an AMPA Receptor (AMPAR) positive cancer in a mamrnalian subject comprising administering an anti-cancer effective amount of an AMPAR
antagonist compound to said subject.
antagonist compound to said subject.
2. The method of claim I. wherein the AMPAR antagonist compound is an allosteric AMPAR antagonist compound.
3. The method of claim 1. wherein thc AMPAR antagonist compound is a Perarnpanel (PMP) compound.
4. The method of clairn 3. wherein the PMP compound is an anti-cancer effective analog or derivative of PMP.
5. The method of claim I. wherein the AMPA Receptor (AMPAR) positive cancer is selected from an AMPA Receptor (AMPAR) positive brain cancer, lung cancer, prostate cancer, breast cancer; skin cancer. liver cancer. thyroid cancer, esophageal cancer. sarcorna. colorectal cancer. bladder cancer. gall bladder cancer, stornach cancer, renal cancer_ ovarian cancer. uterine cancer. cervical cancer. non-Hodgkin's lymphoma: acute rnyelogenous leukemia (AM1.). acute lyrnphocytic leukemia, chronic lymphocytic leukemia (CLL). rnyeloma. rnesothelioma. pancreatic cancer.
Hodgkin's disease. testicular cancer. Waklenstrom's disease. head/neck cancer, tongue cancer. or viral-induced cancer.
Hodgkin's disease. testicular cancer. Waklenstrom's disease. head/neck cancer, tongue cancer. or viral-induced cancer.
6. The method of claim I, wherein the AMPA Receptor (AMPAR) positive cancer is selected from an AMPA Receptor (AMPAR) positive glioblastoma (GBM). or cancer of the breast. pancreas lung or kidney.
7. The method of claim 1. wherein the AMPA Receptor (AMPAR) positive cancer is an AMPA Receptor (AMPAR) positive glioblastoma (GBM).
8. The method of claim I. wherein the AMPAR positive cancer is a glioblastoma (GBM).
9. The rnethod of claim I. wherein the AMPAR antagonist compound is Perampancl (PMP) formulated in an aqueous carrier for parenteral or intravenous administration.
10. The method of claim I. wherein the AMPAR antagonist compound is Perampanel (PMP) formulated in an oral dosage form.
11. The rnethod of clairn 1, wherein the AMPAR antagonist compound mediates a greater than 20% increase in cancer free survival for treated subjects compared to control subjects.
12. The method of claim 1, wherein the AMPAR antagonist cornpound mediates a 50% or greater increase in cancer free survival for subjects compared to control subjects.
13. The method of claim 1. wherein the AMPAR antagonist compound mediates at least a 20% decrease in average size or number of primary tumors or metastases in treated subjects compared to control subjects.
14. The method of claim I_ wherein the AMPAR antagonist compound mediates a 20-50% or larger decrease in average size or number of primary tumors or metastases in treated subjects compared to control subjects.
15. The method of claim 1. wherein the A M PA R antagonist compound is Perampanel (PMP) or an anti-cancer effective prodrug, metabolite, analog or derivative of PMP.
16. The method of claim I. further comprising coordinately administering a secondary anti-cancer agent or therapy to the subject.
17. The method of claim 16, wherein the secondary anti-cancer agent or therapy is selected frorn tubulin depolyrnerizing agents. DNA damaging agents. inhibitors of DNA synthesis. anti-rnetabolics. anti-angiogenic agents, vascular disrupting agents (VDAs). anti-cancer antibodies, endocrine cancer therapies, immuno-modulators, histone deacetylase inhibitors. inhibitors of signal transduction. inhibitors of heat shock proteins. retinoids. growth factors. growth factor receptor modulators, anti-m itotic compounds. anti-inflammatory drugs. and cell cycle regulators.
18. The method of claim 16, wherein the secondary anti-cancer agent or therapy is selected from anti-cancer chemotherapy. surgery and radiation.
19. The method of claim 16. further comprising coordinately adrninistering one or more secondary anti-cancer, chernotherapeutic agent(s) selected from azacitidine, bevaciaimah. bortezomib. eapecitabine. cetuxirnab. clofarabine, dasatinib, decitabine, docetaxel, emend, erlotinib hydrochloride, exemestane, fulvestrant, getitinib, gemcitabine hydrochloride. irnatinib rnesylate, imiquimod, lenalidomide, letrozole .
nelarabine. oxaliplatin, paclitaxel, docetaxel. palifermin, paniturnumab.
pegaspargase, pernetrcxed disodiurn. rituximab. sorafenib tosylate sunitinib rnalate, tarnoxifen citrate. targretin. ternozolomide_ thalidomide. and/or topotecan hydrochloride.
nelarabine. oxaliplatin, paclitaxel, docetaxel. palifermin, paniturnumab.
pegaspargase, pernetrcxed disodiurn. rituximab. sorafenib tosylate sunitinib rnalate, tarnoxifen citrate. targretin. ternozolomide_ thalidomide. and/or topotecan hydrochloride.
20. The method of clairn 16. further comprising coordinately administering one or more secondary anti-cancer agents selected froin an interleukin. interferon, filgrasten, G-CSF. epoetin alfa. erythropoietin. and/or an anti-cancer antibody or antibody fragrnent.
21. The method of claim 16, wherein the AMPAR antagonist compound is Perampanel (PMP) or an anti-cancer effective prodrug, metabolite, analog or derivative of PMP, and the secondary anti-cancer agent is selected from ternozolomide (TMZ), a transcription inhibitor, a telomere disrupting agent. an inhibitor of a gene splicing protein. an indolearnine 2. 3. dioxegenase (IDO) inhibitor, a lapa(inib ditosylate enzyme blacker. and an anti-cancer antibody or antibody fragment.
22. The method of elairn 16. wherein the AMPAR antagonist compound is Perampanel (PMP) or an anti-cancer effective prodrug. metabolite. analog or derivative of PMP, and the secondary anti-cancer therapy emplo) s tumor treating fields or radiation.
23. A pharmaceutical composition comprising an anti-cancer effective amount of an AMPAR antagonist compound and a secondary anti-cancer agent selected frorn a tubulin depolymerizing agent. a DNA darnaging agents. an inhibitor of DNA
synthesis, an anti-metabolic drug. an anti-angiogenic agent. a vascular disrupting agent (VDAs), and anti-cancer antibody or antibody fragment an anti-cancer cytokine_ an anti-cancer hormone, a histonc deacetylase inhibitor, a retinoid, a growth factor. a growth factor receptor modulator. an anti-mitotic compound, or a cell cycle regulator compound.
synthesis, an anti-metabolic drug. an anti-angiogenic agent. a vascular disrupting agent (VDAs), and anti-cancer antibody or antibody fragment an anti-cancer cytokine_ an anti-cancer hormone, a histonc deacetylase inhibitor, a retinoid, a growth factor. a growth factor receptor modulator. an anti-mitotic compound, or a cell cycle regulator compound.
24. The pharmaceutical composition of claim 2ì wherein the secondary anti-cancer agent is selected from ternozolomide (TMZ). a transcription inhibitor. a telomere disrupting agent, an inhibitor of a gene splicing protein. an indoleamine 2. 3.
dioxegenase (IDO) inhibitor. a tapatinib ditosylate enzyme blocker. and an anti-cancer antibody or antibody fragment.
dioxegenase (IDO) inhibitor. a tapatinib ditosylate enzyme blocker. and an anti-cancer antibody or antibody fragment.
25. The method of claim 1. further comprising coordinately administering a secondary therapeutic agent or method to the subject selected from NMDA antagonists;
anti PD-1/PDL-1 therapy: CSF I R inhibitors; cannabinoid drugs; anti-malarials;
Riluzole/troriluzole treatment: antihistamines: biguanides: anti-cancer biologics:
SSRls: TCAs: Ampakines: levetiracetam, or a combination thereof.
anti PD-1/PDL-1 therapy: CSF I R inhibitors; cannabinoid drugs; anti-malarials;
Riluzole/troriluzole treatment: antihistamines: biguanides: anti-cancer biologics:
SSRls: TCAs: Ampakines: levetiracetam, or a combination thereof.
26. The pharmaceutical composition of claim 23 comprising an anti-cancer effective amount of an AMPAR antagonist compound and a secondary therapeutic agent selected from NMDA antagonists: anti PD-1/PDL-1 drugs; CSF1R inhibitors:
cannabinoid drugs; anti-rnalarials: Riluzoleltroriluzole: antihistamines:
biguanides;
anti-cancer biologics: SSR Is: TCAs: Arnpakines; levetiracetam, or a combination thereof.
cannabinoid drugs; anti-rnalarials: Riluzoleltroriluzole: antihistamines:
biguanides;
anti-cancer biologics: SSR Is: TCAs: Arnpakines; levetiracetam, or a combination thereof.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862703951P | 2018-07-27 | 2018-07-27 | |
US62/703,951 | 2018-07-27 | ||
US201962796032P | 2019-01-23 | 2019-01-23 | |
US62/796,032 | 2019-01-23 | ||
PCT/US2019/043525 WO2020023800A1 (en) | 2018-07-27 | 2019-07-25 | Clinical methods and pharmaceutical compositions employing ampa receptor antagonists to treat glioblastoma and other cancers |
Publications (1)
Publication Number | Publication Date |
---|---|
CA3145507A1 true CA3145507A1 (en) | 2020-01-30 |
Family
ID=69182382
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA3145507A Pending CA3145507A1 (en) | 2018-07-27 | 2019-07-25 | Clinical methods and pharmaceutical compositions employing ampa receptor antagonists to treat glioblastoma and other cancers |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP3829567A4 (en) |
AU (1) | AU2019310122A1 (en) |
CA (1) | CA3145507A1 (en) |
WO (1) | WO2020023800A1 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021188431A1 (en) * | 2020-03-16 | 2021-09-23 | Es Therapeutics Llc | Method of treating glioma cancer using tarp gamma 8-dependent ampa receptor antagonists |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1002535A1 (en) * | 1998-10-28 | 2000-05-24 | Hrissanthi Ikonomidou | New use of glutamate antagonists for the treatment of cancer |
US7750024B2 (en) * | 2002-03-29 | 2010-07-06 | Astellas Pharma Inc. | Remedy for glioblastoma |
JP4175846B2 (en) * | 2002-08-08 | 2008-11-05 | 独立行政法人科学技術振興機構 | Inhibition of growth and invasion of brain tumor cells by expression of AMPA-type glutamate receptor subunit |
CN104644592A (en) * | 2013-11-25 | 2015-05-27 | 天津市汉康医药生物技术有限公司 | Perampanel pharmaceutical composition and preparation method thereof |
EP3154954B1 (en) * | 2014-06-10 | 2022-02-09 | Sanford-Burnham Medical Research Institute | Metabotropic glutamate receptor negative allosteric modulators (nams) and uses thereof |
EP3259262A4 (en) * | 2015-02-17 | 2018-08-01 | Mapi Pharma Limited | Process and intermediates for the preparation of perampanel |
WO2016172333A1 (en) * | 2015-04-21 | 2016-10-27 | Teva Pharmaceuticals International Gmbh | A solid state form of perampanel |
-
2019
- 2019-07-25 CA CA3145507A patent/CA3145507A1/en active Pending
- 2019-07-25 WO PCT/US2019/043525 patent/WO2020023800A1/en unknown
- 2019-07-25 EP EP19841117.5A patent/EP3829567A4/en not_active Withdrawn
- 2019-07-25 AU AU2019310122A patent/AU2019310122A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
EP3829567A1 (en) | 2021-06-09 |
WO2020023800A1 (en) | 2020-01-30 |
AU2019310122A1 (en) | 2021-03-18 |
EP3829567A4 (en) | 2022-05-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10183035B2 (en) | Etoposide and prodrugs thereof for use in targeting cancer stem cells | |
JP2021512101A (en) | Combination therapy for the treatment of mastocytosis | |
EP3076977A1 (en) | Combination therapy for treating cancer | |
CA2782527C (en) | Uses of hypoxia-inducible factor inhibitors | |
Yamada et al. | Riluzole enhances the antitumor effects of temozolomide via suppression of MGMT expression in glioblastoma | |
AU2023229592A1 (en) | Combination treatment for hematological cancers | |
US20210308111A1 (en) | Clinical Methods And Pharmaceutical Compositions Employing AMPA Receptor Antagonists To Treat Glioblastoma And Other Cancers | |
CN112294965A (en) | Pharmaceutical compositions of MDM2 inhibitors and their use in the prevention and/or treatment of diseases | |
CA3145507A1 (en) | Clinical methods and pharmaceutical compositions employing ampa receptor antagonists to treat glioblastoma and other cancers | |
JP7071272B2 (en) | Use of pseudofasting to enhance anti-estrogen efficacy in cancer treatment | |
JP6462582B2 (en) | Methods and compositions for the treatment of cancer | |
Lu et al. | Enhanced proliferation inhibition and apoptosis in glioma cells elicited by combination of irinotecan and imatinib | |
AU2018288520B2 (en) | Combination of a Mcl-1 inhibitor and a standard of care treatment for hematologic cancers, uses and pharmaceutical compositions thereof | |
Zhong et al. | Preclinical evaluation of the HDAC inhibitor chidamide in transformed follicular lymphoma | |
US20220151976A1 (en) | Targeting lasp1, eif4a1, eif4b and cxc4 with modulators and combinations thereof for cancer therapy | |
TWI614029B (en) | A novel pharmaceutical composition and uses thereof | |
US20200061054A1 (en) | Use of dianhydrogalactitol or analogs and derivatives in combination with a p53 modulator or a parp inhibitor | |
EP2956132A1 (en) | Modulation of asymmetric proliferation | |
Venney et al. | Epigenetic targeted therapies in hematological malignancies | |
US20210128683A1 (en) | Pharmaceutical compositions and use thereof for relieving resistance due to cancer chemotherapy and enhancing effect of cancer chemotherapy | |
Zhang et al. | Suppression of NSCLC progression via the co-administration of Danusertib, an AURK inhibitor, and KRIBB11, an HSF1 inhibitor | |
Di Leva et al. | Tivantinib induces mitotic death in SHH medulloblastoma cell lines. | |
AU2021200121A1 (en) | Pharmaceutical compositions and use thereof for relieving resistance due to cancer chemotherapy and enhancing effect of cancer chemotherapy | |
Roig | Exploring the benefits of inhibiting HIF and Notch to overcome resistance to cancer therapy | |
EA046068B1 (en) | COMBINED THERAPY FOR THE TREATMENT OF MASTOCYTOSIS |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request |
Effective date: 20220915 |
|
EEER | Examination request |
Effective date: 20220915 |
|
EEER | Examination request |
Effective date: 20220915 |
|
EEER | Examination request |
Effective date: 20220915 |
|
EEER | Examination request |
Effective date: 20220915 |
|
EEER | Examination request |
Effective date: 20220915 |