WO2022175673A1 - Prochlorperazine for use in the treatment of neuroblastoma - Google Patents
Prochlorperazine for use in the treatment of neuroblastoma Download PDFInfo
- Publication number
- WO2022175673A1 WO2022175673A1 PCT/GB2022/050443 GB2022050443W WO2022175673A1 WO 2022175673 A1 WO2022175673 A1 WO 2022175673A1 GB 2022050443 W GB2022050443 W GB 2022050443W WO 2022175673 A1 WO2022175673 A1 WO 2022175673A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- prochlorperazine
- pharmaceutically acceptable
- use according
- acceptable salt
- Prior art date
Links
- WIKYUJGCLQQFNW-UHFFFAOYSA-N prochlorperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 WIKYUJGCLQQFNW-UHFFFAOYSA-N 0.000 title claims abstract description 73
- 229960003111 prochlorperazine Drugs 0.000 title claims abstract description 72
- 206010029260 Neuroblastoma Diseases 0.000 title claims abstract description 53
- 238000011282 treatment Methods 0.000 title claims abstract description 30
- 239000000203 mixture Substances 0.000 claims abstract description 90
- 150000003839 salts Chemical class 0.000 claims abstract description 39
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 claims description 52
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 claims description 52
- 229960004844 lovastatin Drugs 0.000 claims description 52
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 claims description 52
- 239000003814 drug Substances 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- 239000013543 active substance Substances 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical group OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 1
- 210000004027 cell Anatomy 0.000 description 33
- 206010028980 Neoplasm Diseases 0.000 description 31
- 230000003833 cell viability Effects 0.000 description 17
- 229940079593 drug Drugs 0.000 description 14
- 238000000338 in vitro Methods 0.000 description 12
- 101100519293 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pdx-1 gene Proteins 0.000 description 11
- 101150022024 MYCN gene Proteins 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 108700012912 MYCN Proteins 0.000 description 9
- 102000055056 N-Myc Proto-Oncogene Human genes 0.000 description 9
- 108700026495 N-Myc Proto-Oncogene Proteins 0.000 description 9
- 230000009467 reduction Effects 0.000 description 9
- 230000003321 amplification Effects 0.000 description 8
- 238000003199 nucleic acid amplification method Methods 0.000 description 8
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 8
- 102000004121 Annexin A5 Human genes 0.000 description 7
- 108090000672 Annexin A5 Proteins 0.000 description 7
- 230000030833 cell death Effects 0.000 description 7
- 230000004075 alteration Effects 0.000 description 6
- 238000009097 single-agent therapy Methods 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 239000000654 additive Substances 0.000 description 5
- 230000000996 additive effect Effects 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 238000010186 staining Methods 0.000 description 5
- 238000001356 surgical procedure Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 102000003952 Caspase 3 Human genes 0.000 description 4
- 108090000397 Caspase 3 Proteins 0.000 description 4
- 206010017708 Ganglioneuroblastoma Diseases 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 210000000170 cell membrane Anatomy 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- -1 heterocyclic amines Chemical class 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 230000002195 synergetic effect Effects 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 3
- 101100353069 Arabidopsis thaliana PPOX1 gene Proteins 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 101100082669 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) PDX3 gene Proteins 0.000 description 3
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 230000002068 genetic effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 208000019901 Anxiety disease Diseases 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 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 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 101710183548 Pyridoxal 5'-phosphate synthase subunit PdxS Proteins 0.000 description 2
- 101710183564 Pyridoxal 5'-phosphate synthase subunit PdxT Proteins 0.000 description 2
- 102100035459 Pyruvate dehydrogenase protein X component, mitochondrial Human genes 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000003180 beta-lactone group Chemical group 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000036770 blood supply Effects 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 229940105329 carboxymethylcellulose Drugs 0.000 description 2
- 238000003570 cell viability assay Methods 0.000 description 2
- 238000012054 celltiter-glo Methods 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000010579 first pass effect Methods 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000004020 luminiscence type Methods 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
- 239000000463 material Substances 0.000 description 2
- 238000002483 medication Methods 0.000 description 2
- 229940071648 metered dose inhaler Drugs 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 210000004789 organ system Anatomy 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Substances [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- DSKIOWHQLUWFLG-SPIKMXEPSA-N prochlorperazine maleate Chemical compound [H+].[H+].[H+].[H+].[O-]C(=O)\C=C/C([O-])=O.[O-]C(=O)\C=C/C([O-])=O.C1CN(C)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 DSKIOWHQLUWFLG-SPIKMXEPSA-N 0.000 description 2
- 229960002153 prochlorperazine maleate Drugs 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000008223 sterile water Substances 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
- 239000000126 substance Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000011885 synergistic combination Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000035899 viability Effects 0.000 description 2
- HFVMEOPYDLEHBR-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanol Chemical compound C=1C=CC=C(F)C=1C(O)C1=CC=CC=C1 HFVMEOPYDLEHBR-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- QXQAPNSHUJORMC-UHFFFAOYSA-N 1-chloro-4-propylbenzene Chemical compound CCCC1=CC=C(Cl)C=C1 QXQAPNSHUJORMC-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- MPDHRNITJIUNDI-UHFFFAOYSA-N 10h-phenothiazine;piperazine Chemical compound C1CNCCN1.C1=CC=C2NC3=CC=CC=C3SC2=C1 MPDHRNITJIUNDI-UHFFFAOYSA-N 0.000 description 1
- PKHPZNKXOBWFCX-UHFFFAOYSA-N 2-(4-hydroxy-3-phenylbenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)C1=CC=C(O)C(C=2C=CC=CC=2)=C1 PKHPZNKXOBWFCX-UHFFFAOYSA-N 0.000 description 1
- WLAMNBDJUVNPJU-BYPYZUCNSA-N 2-Methylbutanoic acid Natural products CC[C@H](C)C(O)=O WLAMNBDJUVNPJU-BYPYZUCNSA-N 0.000 description 1
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- QISOBCMNUJQOJU-UHFFFAOYSA-N 4-bromo-1h-pyrazole-5-carboxylic acid Chemical compound OC(=O)C=1NN=CC=1Br QISOBCMNUJQOJU-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 235000019489 Almond oil Nutrition 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
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 241001465318 Aspergillus terreus Species 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 239000012583 B-27 Supplement Substances 0.000 description 1
- 102100035080 BDNF/NT-3 growth factors receptor Human genes 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 101150049660 DRD2 gene Proteins 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 1
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 1
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 1
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 102100035108 High affinity nerve growth factor receptor Human genes 0.000 description 1
- 101000596896 Homo sapiens BDNF/NT-3 growth factors receptor Proteins 0.000 description 1
- 101000596894 Homo sapiens High affinity nerve growth factor receptor Proteins 0.000 description 1
- 101000971697 Homo sapiens Kinesin-like protein KIF1B Proteins 0.000 description 1
- 101000692768 Homo sapiens Paired mesoderm homeobox protein 2B Proteins 0.000 description 1
- 101000984033 Homo sapiens Protein lin-28 homolog B Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 1
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 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 1
- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 description 1
- 102100021524 Kinesin-like protein KIF1B Human genes 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
- 108010052014 Liberase Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102100026354 Paired mesoderm homeobox protein 2B Human genes 0.000 description 1
- 235000019483 Peanut oil Nutrition 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
- 108091005804 Peptidases Proteins 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102100025459 Protein lin-28 homolog B Human genes 0.000 description 1
- 101150040459 RAS gene Proteins 0.000 description 1
- 101150076031 RAS1 gene Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 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
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 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
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000002506 anticoagulant protein Substances 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 230000005775 apoptotic pathway Effects 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 239000000987 azo dye Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 150000001277 beta hydroxy acids Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000004641 brain development Effects 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 208000011654 childhood malignant neoplasm Diseases 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 235000012716 cod liver oil Nutrition 0.000 description 1
- 239000003026 cod liver oil Substances 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical compound OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-L ethanedisulfonate group Chemical group C(CS(=O)(=O)[O-])S(=O)(=O)[O-] AFAXGSQYZLGZPG-UHFFFAOYSA-L 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 229940126864 fibroblast growth factor Drugs 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 201000008361 ganglioneuroma Diseases 0.000 description 1
- 230000004077 genetic alteration Effects 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 229960005280 isotretinoin Drugs 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229960004393 lidocaine hydrochloride Drugs 0.000 description 1
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical group CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 230000000869 mutational effect Effects 0.000 description 1
- 230000001400 myeloablative effect Effects 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 230000003988 neural development Effects 0.000 description 1
- 210000003757 neuroblast Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 210000004197 pelvis Anatomy 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 102000016914 ras Proteins Human genes 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000000574 retroperitoneal space Anatomy 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 210000000331 sympathetic ganglia Anatomy 0.000 description 1
- 210000002820 sympathetic nervous system Anatomy 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 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
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
Classifications
-
- 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
- A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—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 sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
-
- 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
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
Definitions
- This invention relates to new uses of prochlorperazine.
- Neuroblastoma is a childhood cancer originating from the neuroblasts of the sympathetic nervous system. It is the most common solid tumour in children after brain tumours. The incidence of neuroblastoma is about 10.54 cases per 1 million per year in children younger than 15 years old. 90% of neuroblastoma cases are diagnosed by age 5.
- MYCN is a transcription factor expressed during development that plays an important role in brain and neural development.
- Other genetic aberrations associated with neuroblastoma include: ALK activation, TERT activation, deletion at lp36 or llql4-23, 17q gain and changes in expression or mutations of KIF1B, PHOX2B, LIN28B, TRKA, TRKB and RAS in relapsed tumours.
- the most common primary tumour site is adrenal (47%), followed by the paraspinal sympathetic ganglia in the abdomen/ retroperitoneum (24%), thorax (15%), pelvis (3%) and neck (3%).
- Neuroblastoma usually occurs sporadically, but familial cases with a prevalence of about 1-2% are also reported.
- patients can be classified into four groups: extremely low risk, low risk, moderate risk and high risk. Patients that are in the low or moderate risk groups can achieve an overall survival rate >95% with the current treatment paradigm. However, patients in the high risk group have a survival rate of around 40-50%.
- Prochlorperazine is a piperazine phenothiazine that blocks the dopaminergic D2 receptors in the brain. It is approved for the treatment of severe nausea and vomiting as well as short term management of anxiety and schizophrenia. Prochlorperazine has the systematic name 2-chloro-10-[3-(4-methyl-l-piperazinyl)propyl]- 10H- phenothiazine.
- the present invention provides a new therapy for neuroblastoma.
- prochlorperazine is effective in treating neuroblastoma.
- a first aspect of the invention is a composition comprising prochlorperazine, or a pharmaceutically acceptable salt thereof, for use in the treatment of neuroblastoma.
- a second aspect of the invention is a kit comprising (i) at least one dose of prochlorperazine, or a pharmaceutically acceptable salt thereof; and optionally (ii) at least one dose of lovastatin, or a pharmaceutically acceptable salt thereof, for simultaneous, separate or sequential use in the treatment of neuroblastoma.
- a third aspect of the invention is a use of a composition comprising prochlorperazine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment of neuroblastoma.
- a fourth aspect of the invention provides a method of treating neuroblastoma comprising administering to a patient a composition comprising prochlorperazine, or a pharmaceutically acceptable salt thereof.
- FIGS 1A-F show the results from the prochlorperazine monotherapy in vitro testing.
- Figures 2A-F show the results from the lovastatin monotherapy in vitro testing.
- Figures 3A-C show the cell death and viability results from prochlorperazine and lovastatin in vitro combination testing.
- Xenografts based on conventional cancer cell lines have been used for decades and while this model system can provide valuable data, cultured cell lines that have adapted to the in vitro microenvironment often differ from the original tumour found in patients.
- Patient-derived xenografts are generated from the subcutaneous or orthotopic implantation of intact patient tumor fragments directly into immunodeficient mice or rats, thereby avoiding in vitro adaptation.
- PDXs have been found to recapitulate the histopathological hallmarks, genetic pathways and mutational patterns of the corresponding patient tumors.
- the in vitro data herein has been generated using the PDX1, PDX2, and PDX3 cell models, as described in Braekeveldt et al, Int. J. Cancer, 2015, E252-E261.
- prochlorperazine inhibits cell viability and increases cell death in neuroblastoma patient-derived xenograft tumours, and is therefore effective at treating neuroblastoma.
- treatment or “treating” as used herein, we refer to therapeutic (curative) treatment, which includes reducing the size of a neuroblastoma tumour or stopping a neuroblastoma tumour increasing in size.
- Patient and “subject” are used interchangeably and refer to the subject that is to be administered the composition comprising lovastatin.
- the subject is a human.
- the patient is a paediatric patient, preferably a paediatric patient 15 years of age and younger, more preferably 10 years of age or younger, most preferably 5 years of age and younger.
- the methods of classification of neuroblastoma tumours are complex and are based on a combination of different factors.
- Described below is a method of classifying neuroblastoma tumours according to the INRGSS system.
- the characteristics described below for each stage are exemplary only.
- the medical practitioner is skilled in diagnosing and would be able to determine the stage of the tumour.
- tumours of neuroblastoma may be described as follows:
- Stage LI The tumour is located only in the area where it started; no image defined risk factors (IDRFs) are found on imaging scans, such as CT or MRI.
- IDRFs image defined risk factors
- Stage L2 The tumour has spread to the tissue nearby the area it started; IDRFs are found on imaging scans, such as CT or MRI.
- Stage M The tumour has spread to other parts of the body (except stage MS, see below).
- Stage MS The tumour has spread to only the skin, liver, and/or bone marrow (less than 10% bone marrow involvement) in patients younger than 18 months.
- the compounds and compositions of the invention can be used to treat or prevent any of the tumours described above.
- the subject may be classified as very low, low, moderate or high risk.
- the subject is classified as moderate or high risk, more preferably high risk.
- Very low-risk neuroblastoma refers to Stage L1/L2 with ganglioneuroma maturing or ganglioneuroblastoma intermixed histology, Stage LI with non-amplified MYCN, or Stage MS in children younger than 18 months of age with no chromosome llq aberration.
- Low-risk neuroblastoma refers to Stage L2 in children younger than 18 months of age with no llq aberration, Stage L2 in children older than 18 months of age with ganglioneuroblastoma nodular or neuroblastoma with differentiating histology and no llq aberration, Stage M in children younger than 18 months without MYCN amplification and hyperdiploidy.
- Moderate-risk neuroblastoma refers to Stage L2 in children younger than 18 months without MYCN amplification with llq aberration, Stage L2 in children older than 18 months with ganglioneuroblastoma nodular or neuroblastoma with differentiating histology with llq aberration, Stage L2 in children older than 18 months with ganglioneuroblastoma nodular or neuroblastoma with poorly differentiated or undifferentiated histology, Stage M in children younger than 12 months with diploidy, or Stage M in children 12 months to 18 months with diploidy.
- High-risk neuroblastoma refers to Stage LI with MYCN amplification, Stage L2 with MYCN amplification, Stage M in children younger than 18 months of age with MYCN amplification, Stage M in children with older than 18 months, Stage MS in children younger than 18 months with llq aberration, or Stage MS in children younger than 18 months of age with MYCN amplification.
- a composition comprising prochlorperazine is used for the treatment of neuroblastoma, wherein the patient has had or is going to have surgery to remove some or all of the neuroblastoma tumour.
- This may be particularly advantageous if the neuroblastoma is large and/or expands across tissue boundaries, so it is difficult to remove it all by surgery and/or a quick removal of at least some of it is desired/beneficial.
- Surgery has its normal meaning in the art. Surgery is an invasive technique with the fundamental principle of physical intervention on organs/organ systems/tissues for diagnostic or therapeutic reasons.
- a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.
- Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as fendizoic, citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulfonic, ethanesulfonic, ethanedisulfonic, salicylic, stearic, benzenesulfonic or p-toluenesulfonic acid.
- Pharmaceutically acceptable bases include alkali metal (e.g.
- the pharmaceutically acceptable salt of prochlorperazine is maleate.
- the pharmaceutically acceptable salt of prochlorperazine is ethanedisulfonate (edisylate).
- the pharmaceutically acceptable salt of prochlorperazine is methanesulfonate (mesylate).
- the present invention is directed to a composition comprising prochlorperazine, or a pharmaceutically acceptable salt thereof, for use in the treatment of neuroblastoma, wherein prochlorperazine is the only active agent in the composition.
- prochlorperazine is the only active agent in the composition.
- only active agent it is meant that the composition does not contain other components which may be used in the treatment of neuroblastoma.
- the present invention is directed to a composition comprising prochlorperazine, or a pharmaceutically acceptable salt thereof, and lovastatin, or a pharmaceutically acceptable salt thereof, for use in the treatment of neuroblastoma.
- the present invention is directed to a composition comprising prochlorperazine, or a pharmaceutically acceptable salt thereof, for use in combination with a second composition comprising lovastatin, or a pharmaceutically acceptable salt thereof, wherein the two compositions are administered to a subject simultaneously, separately or sequentially.
- prochlorperazine As shown by the below in vitro data, prochlorperazine has been identified as showing synergistic effects in the treatment of neuroblastoma, when used in combination with prochlorperazine.
- Lovastatin is a member of the statin class of drugs, it is a fermentation product of Aspergillus terreus. Lovastatin is a lipid lowering drug that acts via inhibiting HMG- CoA reductase, an early and rate limiting step of cholesterol biosynthesis. It is approved for treatment of hyperlipidemias, atherosclerosis, coronary disease and hypercholesterolemia. Lovastatin is formulated as a prodrug in the form of an inactive but cell permeant beta lactone. In vivo and in cells the beta lactone is converted to the active beta hydroxy acid form which is less able to pass through the cell membrane.
- Lovastatin has the following name: (2S)- (lS,3R,7S,8S,8aR)-l,2,3,7,8,8a-hexahydro- 3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-l- naphthalenyl ester, 2-methylbutanoic acid.
- compositions of the invention may contain a pharmaceutically acceptable carrier.
- pharmaceutically acceptable carrier is meant any diluent or excipient, such as fillers or binders, that is compatible with the other ingredients of the compositions, and which is not deleterious to the recipient.
- the pharmaceutically acceptable carrier can be selected on the basis of the desired route of administration, in accordance with standard pharmaceutical practices.
- compositions may be administered in a variety of dosage forms.
- the compositions may be formulated in a format suitable for oral, rectal, parenteral, intranasal or transdermal administration or administration by inhalation or by suppository.
- compositions may be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules.
- the compositions are formulated such that it is suitable for oral administration, for example tablets and capsules.
- Tablets and capsules may be prepared with binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, celluloses or polyvinylpyrrolidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine; lubricants, such as magnesium stearate, talc, polyethylene glycol, or silica; and surfactants, such as sodium lauryl sulfate.
- binding agents for example, syrup, acacia, gelatin, sorbitol, tragacanth, celluloses or polyvinylpyrrolidone
- fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine
- lubricants such as magnesium stearate, talc, polyethylene glycol, or silica
- surfactants such as sodium lauryl sulfate.
- Liquid compositions may contain conventional additives such as suspending agents, for example sorbitol syrup, methyl cellulose, sugar syrup, gelatin, carboxymethyl-cellulose, or edible fats; emulsifying agents and surfactants such as lecithin, or acacia; vegetable oils such as almond oil, coconut oil, cod liver oil, or peanut oil; preservatives such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).
- suspending agents for example sorbitol syrup, methyl cellulose, sugar syrup, gelatin, carboxymethyl-cellulose, or edible fats
- emulsifying agents and surfactants such as lecithin, or acacia
- vegetable oils such as almond oil, coconut oil, cod liver oil, or peanut oil
- preservatives such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).
- Liquid compositions may be encapsulated in, for example,
- compositions may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques.
- compositions may also be administered by inhalation.
- inhaled medications are their direct delivery to the area of rich blood supply in comparison to many medications taken by oral route. Thus, the absorption is very rapid as the alveoli have an enormous surface area and rich blood supply and first pass metabolism is bypassed.
- the present invention also provides an inhalation device containing the compositions of the present invention.
- said device is a metered dose inhaler (MDI), which contains a pharmaceutically acceptable chemical propellant to push the medication out of the inhaler.
- MDI metered dose inhaler
- compositions may also be administered by intranasal administration.
- the nasal cavity's highly permeable tissue is very receptive to medication and absorbs it quickly and efficiently.
- Nasal drug delivery is less painful and invasive than injections, generating less anxiety among patients. By this method absorption is very rapid and first pass metabolism is usually bypassed, thus reducing inter-patient variability.
- the present invention also provides an intranasal device containing the composition according to the present invention.
- compositions may also be administered by transdermal administration.
- transdermal and transmucosal patches for topical delivery, transdermal and transmucosal patches, creams, ointments, jellies, solutions or suspensions may be employed.
- the present invention therefore also provides a transdermal patch containing the compositions.
- compositions may also be administered by sublingual administration.
- present invention therefore also provides a sub-lingual tablet comprising the compositions.
- compositions may also be formulated with an agent which reduces degradation of the substance by processes other than the normal metabolism of the patient, such as anti-bacterial agents, or inhibitors of protease enzymes which might be the present in the patient or in commensural or parasite organisms living on or within the patient, and which are capable of degrading the compound.
- an agent which reduces degradation of the substance by processes other than the normal metabolism of the patient such as anti-bacterial agents, or inhibitors of protease enzymes which might be the present in the patient or in commensural or parasite organisms living on or within the patient, and which are capable of degrading the compound.
- Liquid dispersions for oral administration may be syrups, emulsions and suspensions.
- Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
- the suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
- Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
- compositions are administered in an effective amount to treat neuroblastoma.
- An effective dose will be apparent to one skilled in the art, and is dependent on a number of factors including age, sex, weigh, which the medical practitioner will be capable of determining.
- compositions and kits of the present invention provide for the administration of more than one drug, and they can be administered simultaneously, sequentially or separately. It is not necessary that they are packed together (but this is one embodiment of the invention). It is also not necessary that they are administered at the same time.
- “separate” administration means that the drugs are administered as part of the same overall dosage regimen (which could comprise a number of days), but preferably on the same day.
- “simultaneously” means that the drugs are to be taken together or formulated as a single composition.
- “sequentially” means that the drugs are administered at about the same time, and preferably within about 1 hour of each other.
- the drugs are administered simultaneously i.e. taken together or formulated as a single composition. Most preferably, they are formulated as a single composition.
- the composition comprises 1 mg to 40 mg, more preferably 5 mg to 35 mg, yet more preferably 10 mg to 30 mg prochlorperazine.
- the composition may be administered once a day, twice a day, three times a day or four times a day.
- the composition is administered at least once a day.
- it is administered as a single daily dose.
- the single daily dose is 1 mg to 40 mg, more preferably 5 mg to 35 mg, yet more preferably 10 mg to 30 mg of prochlorperazine.
- Exemplary doses are 5, 10, 20, or 40 mg of prochlorperazine.
- the composition further comprises lovastatin or a pharmaceutically acceptable salt thereof, wherein the composition comprises 1 mg to 100 mg, preferably 5 mg to 90 mg, more preferably 10 mg to 80 mg, yet more preferably 20 mg to 60 mg of lovastatin.
- the lovastatin or a pharmaceutically acceptable salt thereof is administered in a second composition, wherein the second composition comprises 1 mg to 100 mg, preferably 5 mg to 90 mg, more preferably 10 mg to 80 mg, yet more preferably 20 mg to 60 mg of lovastatin.
- compositions comprising prochlorperazine and the second composition are a single daily dose.
- the two compositions are administered simultaneously i.e. prochlorperazine and lovastatin are taken together.
- the compositions may also be administered sequentially i.e. at about the same time, and preferably within about 1 hour of each other.
- the composition is administered twice daily.
- each dose is 0.5 mg to 20 mg, more preferably 2.5 mg to 17.5 mg, yet more preferably 5 mg to 15 mg of prochlorperazine.
- Exemplary doses are 5, 10, or 20 mg of prochlorperazine.
- each dose comprises 0.5 to 50 mg, preferably 2.5 to 45 mg, more preferably 5 to 40 mg, yet more preferably 10 mg to 30 mg of lovastatin.
- each dose comprises 0.5 to 50 mg, preferably 2.5 to 45 mg, more preferably 5 to 40 mg, yet more preferably 10 mg to 30 mg lovastatin.
- Each dose or composition may be administered separately or sequentially i.e. at about the same time, and preferably within about 1 hour of each other.In an embodiment of the invention, the composition is administered three times daily.
- each dose is 0.3 mg to 13 mg, more preferably 1.7 mg to 12 mg, more preferably 3 mg to 10 mg of prochlorperazine.
- Exemplary doses are 1, 5, or 10 mg of prochlorperazine.
- each dose comprises 0.3 to 33 mg lovastatin.
- each dose comprises 0.3 mg to 33 mg, more preferably 1.5 mg to 30 mg, more preferably 3 mg to 30 mg, yet more preferably 6 to 20 mg of lovastatin.
- Each dose or composition may be administered separately or sequentially i.e. at about the same time, and preferably within about 1 hour of each other.
- the dosage regime is such that the total daily dosage of prochlorperazine does not exceed 40 mg.
- the effective dose of prochlorperazine results in a concentration of 1 to 10 pM, preferably 1 to 5 pM, more preferably 1 to 4 pM in cells.
- the composition comprising prochlorperazine is used in a chronic dosage regime i.e. chronic, long-term treatment.
- a chronic dosage regime i.e. chronic, long-term treatment.
- the regime lasts for at least one month, suitably at least two months, such as at least three months.
- the present invention also relates to a kit comprising: (i) at least one dose of prochlorperazine, or a pharmaceutically acceptable salt thereof; and optionally (ii) at least one dose of lovastatin, or a pharmaceutically acceptable salt thereof, for simultaneous, separate or sequential use in the treatment of neuroblastoma.
- the present invention also relates to the use of a composition comprising prochlorperazine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment of neuroblastoma.
- This embodiment of the invention may have any of the preferred features described above.
- the present invention also relates to a method of treating neuroblastoma comprising administering to a patient a composition comprising prochlorperazine or a pharmaceutically acceptable salt thereof.
- This embodiment of the invention may have any of the preferred features described above.
- the method of administration may be according to any of the routes described above.
- the present invention further relates to a method of treating neuroblastoma comprising administering to the patient a composition comprising prochlorperazine or a pharmaceutically acceptable salt thereof, and a second composition comprising lovastatin, or a pharmaceutically acceptable salt thereof, wherein the two compositions are administered to the patient simultaneously, separately or sequentially.
- This embodiment of the invention may have any of the preferred features described above.
- the method of administration may be according to any of the routes described above.
- the present invention also embraces prodrugs which react in vivo to give a compound of the present invention.
- Example 1 Monotherapy in vitro drug testing of prochlorperazine and lovastatin
- prochlorperazine and lovastatin were investigated and their ability to inhibit cell growth utilizing neuroblastoma patient-derived xenograft tumours grown in vitro (PDX1, PDX2 and PDX3).
- tumours were grown in male or female NSG mice, mice were housed under pathogen free conditions and given access to food and water ab libitum. Animals were sacrificed, tumour tissues excised and digested for 45 mins at 37°C with Liberase (0.15mg/ml).
- Dissociated tissue was passed through a 70pm cell strainer and cultured in non-adherent plates as tumour spheroids at 37°C in a humidified atmosphere with 5% CO2 in the following culture medium: Dulbecco's Modified Eagle's medium DMEM/F12 medium with glutamine, 100 IU/ml penicillin and 100 pg/ml of streptomycin, 2% B27 supplement, 40 ng/ml of basic fibroblast growth factor (FGF) 2 and 20 ng/ml of epidermal growth factor (EGF). Directly upon seeding cells were treated with the compounds solubilised in DMSO, then cultured for 3 or 7 days.
- Dulbecco's Modified Eagle's medium DMEM/F12 medium with glutamine, 100 IU/ml penicillin and 100 pg/ml of streptomycin, 2% B27 supplement, 40 ng/ml of basic fibroblast growth factor (FGF) 2 and 20 ng/ml of epidermal growth factor
- Cell viability was quantified using the CellTiter-Glo ® luminescence Cell Viability Assay. Using this assay the number of metabolically active viable cells present in a culture can be determined based on the concentration of ATP. The luminescent signal produced is proportional to the amount of ATP present.
- Prochlorperazine maleate and lovastatin had a purity of >95%. Drugs were tested in triplicate, at a minimum of 6 concentrations, top concentration of IOmM (free- base equivalent). Cell viability readouts were normalized to DMSO treated controls, concentration-response curves were plotted and IC50 and R2 values were calculated using GraphPad Prism 8.4.3. Results
- Viable cells in the culture were quantified using the trypan blue staining assay.
- Trypan blue is an azo dye that is cell membrane impermeable that can only enter dead cells that have a permeable membrane. The dye binds to intracellular proteins and therefore dead cells are stained blue. The number of live (unstained) and dead (stained) cells were then quantified, and the percentage of viable cells calculated.
- Annexin V/PI staining cells were incubated with fluorescent annexin V and PI, a human vascular anti-coagulant that binds to phospholipid phosphatidylserine (PS).
- PS is normally found on the inner leaflets of the plasma membrane, during apoptosis these move to the outer leaflet of the plasma membrane. Therefore, annexin V only binds to apoptotic cells.
- PI is a red fluorescent stain that binds to DNA and is impermeable to live cells, therefore only binds to dead cells.
- Annexin V/PI assay was carried out according to manufacturer's instructions.
- Caspase 3 an apoptosis marker was quantified using the NucView® Caspase-3 assay kit in live cells according to manufacturer's instructions. Cells were counted on a FACSverse flow cytometer and populations gated and quantified.
- Concentration response combination studies were carried out in the PDX 1, 2 and 3 cell models.
- Cells were cultured using the same protocol as described for the monotherapy studies. At seeding, cells were treated with lovastatin combined with prochlorperazine in a 6x6 concentration matrix of increasing concentrations of both drugs. Cells were cultured for 3 or 7 days; cell viability was quantified using the CellTiter-Glo® luminescence Cell Viability Assay.
- Prochlorperazine maleate and lovastatin had a purity of >95%. Drugs were tested in triplicate, the top concentration of lovastatin was 20pM, the top concentration of prochlorperazine was 5pM (free-base equivalent).
- Prochlorperazine inhibits the cell viability and increases cell death in neuroblastoma cell lines, and is therefore effective at treating neuroblastoma.
- the reduction in cell viability can be further enhanced when a combination of prochlorperazine and lovastatin is used.
- the combination treatment leads to synergistic increases (i.e. greater than the expected additive values) in cell death and reduction in cell viability, and this synergy is quantified by the ZIP synergy scores.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to compositions comprising prochlorperazine, or a pharmaceutically acceptable salt thereof, for use in the treatment of neuroblastoma.
Description
PROCHLORPERAZINE FOR USE IN THE TREATMENT OF NEUROBLASTOMA
Field of the invention
This invention relates to new uses of prochlorperazine.
Background of the invention
Neuroblastoma is a childhood cancer originating from the neuroblasts of the sympathetic nervous system. It is the most common solid tumour in children after brain tumours. The incidence of neuroblastoma is about 10.54 cases per 1 million per year in children younger than 15 years old. 90% of neuroblastoma cases are diagnosed by age 5.
The genetic causation of neuroblastoma, like most cancers, is complex and heterogeneous. A common event in patients with high risk neuroblastoma and associated with poor prognosis is the amplification of the MYCN gene. MYCN is a transcription factor expressed during development that plays an important role in brain and neural development. Other genetic aberrations associated with neuroblastoma include: ALK activation, TERT activation, deletion at lp36 or llql4-23, 17q gain and changes in expression or mutations of KIF1B, PHOX2B, LIN28B, TRKA, TRKB and RAS in relapsed tumours. The most common primary tumour site is adrenal (47%), followed by the paraspinal sympathetic ganglia in the abdomen/ retroperitoneum (24%), thorax (15%), pelvis (3%) and neck (3%). Neuroblastoma usually occurs sporadically, but familial cases with a prevalence of about 1-2% are also reported. Based on a number of factors including age at diagnosis, histopathological classification and the genetic profile of the tumour, patients can be classified into four groups: extremely low risk, low risk, moderate risk and high risk. Patients that are in the low or moderate risk groups can achieve an overall survival rate >95% with the current treatment paradigm. However, patients in the high risk group have a survival rate of around 40-50%.
At present there is no effective therapy to treat neuroblastoma patients who are in the high risk category. The current treatment path for patients that have high risk tumours is intensive and multimodal; they receive high-dose chemotherapy, radiotherapy, surgery, myeloablative therapy and stem cell transplant, isotretinoin differentiation therapy and immunotherapy (anti-GD2, IL-l/GM-CSF). Despite multiple therapeutic options for these patients the survival rate is still 40-50%, meaning there is a high unmet need for new therapeutics for patients in this risk category, that can prolong life with reduced toxicity.
Prochlorperazine is a piperazine phenothiazine that blocks the dopaminergic D2 receptors in the brain. It is approved for the treatment of severe nausea and vomiting
as well as short term management of anxiety and schizophrenia. Prochlorperazine has the systematic name 2-chloro-10-[3-(4-methyl-l-piperazinyl)propyl]- 10H- phenothiazine.
Summary of the invention
The present invention provides a new therapy for neuroblastoma. As will be evident from the in vitro data presented below, prochlorperazine is effective in treating neuroblastoma.
Accordingly, a first aspect of the invention is a composition comprising prochlorperazine, or a pharmaceutically acceptable salt thereof, for use in the treatment of neuroblastoma.
A second aspect of the invention is a kit comprising (i) at least one dose of prochlorperazine, or a pharmaceutically acceptable salt thereof; and optionally (ii) at least one dose of lovastatin, or a pharmaceutically acceptable salt thereof, for simultaneous, separate or sequential use in the treatment of neuroblastoma.
A third aspect of the invention is a use of a composition comprising prochlorperazine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment of neuroblastoma.
A fourth aspect of the invention provides a method of treating neuroblastoma comprising administering to a patient a composition comprising prochlorperazine, or a pharmaceutically acceptable salt thereof.
Description of the figures
Figures 1A-F show the results from the prochlorperazine monotherapy in vitro testing.
Figures 2A-F show the results from the lovastatin monotherapy in vitro testing.
Figures 3A-C show the cell death and viability results from prochlorperazine and lovastatin in vitro combination testing.
Detailed description
Xenografts based on conventional cancer cell lines have been used for decades and while this model system can provide valuable data, cultured cell lines that have adapted to the in vitro microenvironment often differ from the original tumour found in patients. Patient-derived xenografts (PDXs) are generated from the subcutaneous or orthotopic implantation of intact patient tumor fragments directly into immunodeficient mice or rats, thereby avoiding in vitro adaptation. Importantly, PDXs have been found to recapitulate the histopathological hallmarks, genetic pathways and mutational patterns of the corresponding patient tumors. The in vitro data herein has
been generated using the PDX1, PDX2, and PDX3 cell models, as described in Braekeveldt et al, Int. J. Cancer, 2015, E252-E261.
In the present invention, and as demonstrated by the in vitro data herein, prochlorperazine inhibits cell viability and increases cell death in neuroblastoma patient-derived xenograft tumours, and is therefore effective at treating neuroblastoma.
By the term "treatment" or "treating" as used herein, we refer to therapeutic (curative) treatment, which includes reducing the size of a neuroblastoma tumour or stopping a neuroblastoma tumour increasing in size.
"Patient" and "subject" are used interchangeably and refer to the subject that is to be administered the composition comprising lovastatin. Preferably the subject is a human. In one embodiment the patient is a paediatric patient, preferably a paediatric patient 15 years of age and younger, more preferably 10 years of age or younger, most preferably 5 years of age and younger.
The methods of classification of neuroblastoma tumours are complex and are based on a combination of different factors.
Described below is a method of classifying neuroblastoma tumours according to the INRGSS system. The characteristics described below for each stage are exemplary only. There are other established systems for classifying the tumours, such as the INSS system, among others. The medical practitioner is skilled in diagnosing and would be able to determine the stage of the tumour.
According to the INRGSS system, the tumours of neuroblastoma may be described as follows:
Stage LI : The tumour is located only in the area where it started; no image defined risk factors (IDRFs) are found on imaging scans, such as CT or MRI.
Stage L2: The tumour has spread to the tissue nearby the area it started; IDRFs are found on imaging scans, such as CT or MRI.
Stage M : The tumour has spread to other parts of the body (except stage MS, see below).
Stage MS: The tumour has spread to only the skin, liver, and/or bone marrow (less than 10% bone marrow involvement) in patients younger than 18 months.
Suitably the compounds and compositions of the invention can be used to treat or prevent any of the tumours described above.
Suitably the subject may be classified as very low, low, moderate or high risk. Preferably, the subject is classified as moderate or high risk, more preferably high risk.
Very low-risk neuroblastoma refers to Stage L1/L2 with ganglioneuroma maturing or ganglioneuroblastoma intermixed histology, Stage LI with non-amplified
MYCN, or Stage MS in children younger than 18 months of age with no chromosome llq aberration.
Low-risk neuroblastoma refers to Stage L2 in children younger than 18 months of age with no llq aberration, Stage L2 in children older than 18 months of age with ganglioneuroblastoma nodular or neuroblastoma with differentiating histology and no llq aberration, Stage M in children younger than 18 months without MYCN amplification and hyperdiploidy.
Moderate-risk neuroblastoma refers to Stage L2 in children younger than 18 months without MYCN amplification with llq aberration, Stage L2 in children older than 18 months with ganglioneuroblastoma nodular or neuroblastoma with differentiating histology with llq aberration, Stage L2 in children older than 18 months with ganglioneuroblastoma nodular or neuroblastoma with poorly differentiated or undifferentiated histology, Stage M in children younger than 12 months with diploidy, or Stage M in children 12 months to 18 months with diploidy.
High-risk neuroblastoma refers to Stage LI with MYCN amplification, Stage L2 with MYCN amplification, Stage M in children younger than 18 months of age with MYCN amplification, Stage M in children with older than 18 months, Stage MS in children younger than 18 months with llq aberration, or Stage MS in children younger than 18 months of age with MYCN amplification.
In one embodiment, a composition comprising prochlorperazine is used for the treatment of neuroblastoma, wherein the patient has had or is going to have surgery to remove some or all of the neuroblastoma tumour. This may be particularly advantageous if the neuroblastoma is large and/or expands across tissue boundaries, so it is difficult to remove it all by surgery and/or a quick removal of at least some of it is desired/beneficial.
The term "surgery" has its normal meaning in the art. Surgery is an invasive technique with the fundamental principle of physical intervention on organs/organ systems/tissues for diagnostic or therapeutic reasons.
As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as fendizoic, citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulfonic, ethanesulfonic, ethanedisulfonic, salicylic, stearic, benzenesulfonic or p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aryl amines or heterocyclic amines. In a preferred embodiment, the pharmaceutically acceptable salt of prochlorperazine is maleate. In an alternative
preferred embodiment, the pharmaceutically acceptable salt of prochlorperazine is ethanedisulfonate (edisylate). In a further preferred embodiment, the pharmaceutically acceptable salt of prochlorperazine is methanesulfonate (mesylate).
In an alternative embodiment, the present invention is directed to a composition comprising prochlorperazine, or a pharmaceutically acceptable salt thereof, for use in the treatment of neuroblastoma, wherein prochlorperazine is the only active agent in the composition. By only active agent it is meant that the composition does not contain other components which may be used in the treatment of neuroblastoma.
In an alternative embodiment, the present invention is directed to a composition comprising prochlorperazine, or a pharmaceutically acceptable salt thereof, and lovastatin, or a pharmaceutically acceptable salt thereof, for use in the treatment of neuroblastoma.
In an alternative embodiment, the present invention is directed to a composition comprising prochlorperazine, or a pharmaceutically acceptable salt thereof, for use in combination with a second composition comprising lovastatin, or a pharmaceutically acceptable salt thereof, wherein the two compositions are administered to a subject simultaneously, separately or sequentially.
As shown by the below in vitro data, prochlorperazine has been identified as showing synergistic effects in the treatment of neuroblastoma, when used in combination with prochlorperazine.
Lovastatin is a member of the statin class of drugs, it is a fermentation product of Aspergillus terreus. Lovastatin is a lipid lowering drug that acts via inhibiting HMG- CoA reductase, an early and rate limiting step of cholesterol biosynthesis. It is approved for treatment of hyperlipidemias, atherosclerosis, coronary disease and hypercholesterolemia. Lovastatin is formulated as a prodrug in the form of an inactive but cell permeant beta lactone. In vivo and in cells the beta lactone is converted to the active beta hydroxy acid form which is less able to pass through the cell membrane. Lovastatin has the following name: (2S)- (lS,3R,7S,8S,8aR)-l,2,3,7,8,8a-hexahydro- 3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-l- naphthalenyl ester, 2-methylbutanoic acid.
The compositions of the invention may contain a pharmaceutically acceptable carrier. By "pharmaceutically acceptable carrier" is meant any diluent or excipient, such as fillers or binders, that is compatible with the other ingredients of the compositions, and which is not deleterious to the recipient. The pharmaceutically acceptable carrier can be selected on the basis of the desired route of administration, in accordance with standard pharmaceutical practices.
In the present invention, the compositions may be administered in a variety of dosage forms. In one embodiment, the compositions may be formulated in a format
suitable for oral, rectal, parenteral, intranasal or transdermal administration or administration by inhalation or by suppository.
The compositions may be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. Preferably, the compositions are formulated such that it is suitable for oral administration, for example tablets and capsules. Tablets and capsules may be prepared with binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, celluloses or polyvinylpyrrolidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine; lubricants, such as magnesium stearate, talc, polyethylene glycol, or silica; and surfactants, such as sodium lauryl sulfate. Liquid compositions may contain conventional additives such as suspending agents, for example sorbitol syrup, methyl cellulose, sugar syrup, gelatin, carboxymethyl-cellulose, or edible fats; emulsifying agents and surfactants such as lecithin, or acacia; vegetable oils such as almond oil, coconut oil, cod liver oil, or peanut oil; preservatives such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). Liquid compositions may be encapsulated in, for example, gelatin to provide a unit dosage form.
The compositions may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques.
The compositions may also be administered by inhalation. An advantage of inhaled medications is their direct delivery to the area of rich blood supply in comparison to many medications taken by oral route. Thus, the absorption is very rapid as the alveoli have an enormous surface area and rich blood supply and first pass metabolism is bypassed.
The present invention also provides an inhalation device containing the compositions of the present invention. Typically said device is a metered dose inhaler (MDI), which contains a pharmaceutically acceptable chemical propellant to push the medication out of the inhaler.
The compositions may also be administered by intranasal administration. The nasal cavity's highly permeable tissue is very receptive to medication and absorbs it quickly and efficiently. Nasal drug delivery is less painful and invasive than injections, generating less anxiety among patients. By this method absorption is very rapid and first pass metabolism is usually bypassed, thus reducing inter-patient variability. Further, the present invention also provides an intranasal device containing the composition according to the present invention.
The compositions may also be administered by transdermal administration. For topical delivery, transdermal and transmucosal patches, creams, ointments, jellies,
solutions or suspensions may be employed. The present invention therefore also provides a transdermal patch containing the compositions.
The compositions may also be administered by sublingual administration. The present invention therefore also provides a sub-lingual tablet comprising the compositions.
The compositions may also be formulated with an agent which reduces degradation of the substance by processes other than the normal metabolism of the patient, such as anti-bacterial agents, or inhibitors of protease enzymes which might be the present in the patient or in commensural or parasite organisms living on or within the patient, and which are capable of degrading the compound.
Liquid dispersions for oral administration may be syrups, emulsions and suspensions.
Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
In an embodiment of the invention, the compositions are administered in an effective amount to treat neuroblastoma. An effective dose will be apparent to one skilled in the art, and is dependent on a number of factors including age, sex, weigh, which the medical practitioner will be capable of determining.
The compositions and kits of the present invention provide for the administration of more than one drug, and they can be administered simultaneously, sequentially or separately. It is not necessary that they are packed together (but this is one embodiment of the invention). It is also not necessary that they are administered at the same time. As used herein, "separate" administration means that the drugs are administered as part of the same overall dosage regimen (which could comprise a number of days), but preferably on the same day. As used herein "simultaneously" means that the drugs are to be taken together or formulated as a single composition. As used herein, "sequentially" means that the drugs are administered at about the same time, and preferably within about 1 hour of each other.
Preferably, the drugs are administered simultaneously i.e. taken together or formulated as a single composition. Most preferably, they are formulated as a single
composition. In a preferred embodiment, the composition comprises 1 mg to 40 mg, more preferably 5 mg to 35 mg, yet more preferably 10 mg to 30 mg prochlorperazine. The composition may be administered once a day, twice a day, three times a day or four times a day.
In an embodiment of the invention, the composition is administered at least once a day. Preferably it is administered as a single daily dose. Preferably the single daily dose is 1 mg to 40 mg, more preferably 5 mg to 35 mg, yet more preferably 10 mg to 30 mg of prochlorperazine. Exemplary doses are 5, 10, 20, or 40 mg of prochlorperazine.
In another embodiment, the composition further comprises lovastatin or a pharmaceutically acceptable salt thereof, wherein the composition comprises 1 mg to 100 mg, preferably 5 mg to 90 mg, more preferably 10 mg to 80 mg, yet more preferably 20 mg to 60 mg of lovastatin.
Alternatively the lovastatin or a pharmaceutically acceptable salt thereof is administered in a second composition, wherein the second composition comprises 1 mg to 100 mg, preferably 5 mg to 90 mg, more preferably 10 mg to 80 mg, yet more preferably 20 mg to 60 mg of lovastatin.
Suitably the composition comprising prochlorperazine and the second composition are a single daily dose. Suitably the two compositions are administered simultaneously i.e. prochlorperazine and lovastatin are taken together. The compositions may also be administered sequentially i.e. at about the same time, and preferably within about 1 hour of each other.
In an embodiment of the invention, the composition is administered twice daily. Preferably each dose is 0.5 mg to 20 mg, more preferably 2.5 mg to 17.5 mg, yet more preferably 5 mg to 15 mg of prochlorperazine. Exemplary doses are 5, 10, or 20 mg of prochlorperazine. When the composition further comprises lovastatin, or a pharmaceutically acceptable salt thereof, as described above, each dose comprises 0.5 to 50 mg, preferably 2.5 to 45 mg, more preferably 5 to 40 mg, yet more preferably 10 mg to 30 mg of lovastatin. Alternatively, when the composition is administered with the second composition comprising lovastatin, or a pharmaceutically acceptable salt thereof, as described above, each dose comprises 0.5 to 50 mg, preferably 2.5 to 45 mg, more preferably 5 to 40 mg, yet more preferably 10 mg to 30 mg lovastatin. Each dose or composition may be administered separately or sequentially i.e. at about the same time, and preferably within about 1 hour of each other.In an embodiment of the invention, the composition is administered three times daily. Preferably each dose is 0.3 mg to 13 mg, more preferably 1.7 mg to 12 mg, more preferably 3 mg to 10 mg of prochlorperazine. Exemplary doses are 1, 5, or 10 mg of prochlorperazine. When the composition further comprises lovastatin, or a pharmaceutically acceptable salt
thereof, as described above, each dose comprises 0.3 to 33 mg lovastatin. Alternatively, when the composition is administered with the second composition comprising lovastatin, or a pharmaceutically acceptable salt thereof, as described above, each dose comprises 0.3 mg to 33 mg, more preferably 1.5 mg to 30 mg, more preferably 3 mg to 30 mg, yet more preferably 6 to 20 mg of lovastatin. Each dose or composition may be administered separately or sequentially i.e. at about the same time, and preferably within about 1 hour of each other.
Preferably, the dosage regime is such that the total daily dosage of prochlorperazine does not exceed 40 mg.
Suitably the effective dose of prochlorperazine results in a concentration of 1 to 10 pM, preferably 1 to 5 pM, more preferably 1 to 4 pM in cells.
In order to treat neuroblastoma, the composition comprising prochlorperazine is used in a chronic dosage regime i.e. chronic, long-term treatment. Suitably the regime lasts for at least one month, suitably at least two months, such as at least three months.
The present invention also relates to a kit comprising: (i) at least one dose of prochlorperazine, or a pharmaceutically acceptable salt thereof; and optionally (ii) at least one dose of lovastatin, or a pharmaceutically acceptable salt thereof, for simultaneous, separate or sequential use in the treatment of neuroblastoma.
The present invention also relates to the use of a composition comprising prochlorperazine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment of neuroblastoma. This embodiment of the invention may have any of the preferred features described above.
The present invention also relates to a method of treating neuroblastoma comprising administering to a patient a composition comprising prochlorperazine or a pharmaceutically acceptable salt thereof.
This embodiment of the invention may have any of the preferred features described above. The method of administration may be according to any of the routes described above.
The present invention further relates to a method of treating neuroblastoma comprising administering to the patient a composition comprising prochlorperazine or a pharmaceutically acceptable salt thereof, and a second composition comprising lovastatin, or a pharmaceutically acceptable salt thereof, wherein the two compositions are administered to the patient simultaneously, separately or sequentially.
This embodiment of the invention may have any of the preferred features described above. The method of administration may be according to any of the routes described above.
For the avoidance of doubt, the present invention also embraces prodrugs which react in vivo to give a compound of the present invention.
Experimental Section
Example 1: Monotherapy in vitro drug testing of prochlorperazine and lovastatin
The individual efficacies of prochlorperazine and lovastatin were investigated and their ability to inhibit cell growth utilizing neuroblastoma patient-derived xenograft tumours grown in vitro (PDX1, PDX2 and PDX3).
Methods
All in vitro preclinical models were derived from patient derived xenograft tumours and cultured ex vivo. The establishment of PDX 1, 2 &. 3 was described in Braekeveldt et a/, Int. J. Cancer, 2015, E252-E261. All models had MYCN amplification and are therefore representative of high-risk patients.
PDX 1, 2 &. 3 tumours were grown in male or female NSG mice, mice were housed under pathogen free conditions and given access to food and water ab libitum. Animals were sacrificed, tumour tissues excised and digested for 45 mins at 37°C with Liberase (0.15mg/ml). Dissociated tissue was passed through a 70pm cell strainer and cultured in non-adherent plates as tumour spheroids at 37°C in a humidified atmosphere with 5% CO2 in the following culture medium: Dulbecco's Modified Eagle's medium DMEM/F12 medium with glutamine, 100 IU/ml penicillin and 100 pg/ml of streptomycin, 2% B27 supplement, 40 ng/ml of basic fibroblast growth factor (FGF) 2 and 20 ng/ml of epidermal growth factor (EGF). Directly upon seeding cells were treated with the compounds solubilised in DMSO, then cultured for 3 or 7 days. Cell viability was quantified using the CellTiter-Glo® luminescence Cell Viability Assay. Using this assay the number of metabolically active viable cells present in a culture can be determined based on the concentration of ATP. The luminescent signal produced is proportional to the amount of ATP present.
Prochlorperazine maleate and lovastatin had a purity of >95%. Drugs were tested in triplicate, at a minimum of 6 concentrations, top concentration of IOmM (free- base equivalent).
Cell viability readouts were normalized to DMSO treated controls, concentration-response curves were plotted and IC50 and R2 values were calculated using GraphPad Prism 8.4.3. Results
Reduction in cell viability bv prochlorperazine
Results for prochlorperazine treatment in neuroblastoma cell lines can be seen in Figures 1A-F. Prochlorperazine inhibited the growth of PDX 1, 2 and 3 after 3 and 7 days in culture. Prochlorperazine inhibited cell viability by 50% in all cell models at both timepoints at concentrations of 3.9pM or less.
Reduction in cell viability bv lovastatin
Results for lovastatin treatment in neuroblastoma cell lines can be seen in Figures 2A-F. Lovastatin inhibited the growth of PDX 1, 2 81 3 after 3 days in culture. After 7 days of culture lovastatin inhibited the viability of all three cell lines at an IC50 of 0.84pM (PDX 1), 2.67pM (PDX 2) and 0.15pM (PDX3).
Example 2 - Fixed Concentration Combination Study of prochlorperazine and lovastatin
Materials and Methods Cell culture conditions
Fixed concentration combination studies were carried out using PDX 1 &. 2 cell models. Cells were cultured using the same protocol as described for the monotherapy studies. Cells were treated for 7 days with lovastatin and prochlorperazine at a fixed concentration indicated in Table 1.
The fixed concentrations were equivalent to theIC50 values of each agent at 7 days as monotherapies in the two models.
Table 1 - Concentrations of lovastatin and prochlorperazine used in the combination study
Trypan blue staining assay
Viable cells in the culture were quantified using the trypan blue staining assay. Trypan blue is an azo dye that is cell membrane impermeable that can only enter dead cells that have a permeable membrane. The dye binds to intracellular proteins and therefore dead cells are stained blue. The number of live (unstained) and dead (stained) cells were then quantified, and the percentage of viable cells calculated.
Flow cytometry
Cell death was quantified by Annexin V/Propidium iodide (PI) and caspase 3 staining using flow cytometry. For Annexin V/PI staining cells were incubated with fluorescent annexin V and PI, a human vascular anti-coagulant that binds to phospholipid phosphatidylserine (PS). PS is normally found on the inner leaflets of the plasma membrane, during apoptosis these move to the outer leaflet of the plasma membrane. Therefore, annexin V only binds to apoptotic cells. PI is a red fluorescent stain that binds to DNA and is impermeable to live cells, therefore only binds to dead cells. Annexin V/PI assay was carried out according to manufacturer's instructions. Caspase 3 an apoptosis marker was quantified using the NucView® Caspase-3 assay kit in live cells according to manufacturer's instructions. Cells were counted on a FACSverse flow cytometer and populations gated and quantified.
Data Analysis
Graphs of live and dead cell values were plotted using GraphPad Prism 8.4.2.
Results
Prochlorperazine and lovastatin
The results can be seen in Figures 3A-C. A reduction in cell viability and increase in cell death (annexin V/PI) was observed in both PDX 1 and PDX 2 cells treated with lovastatin and prochlorperazine as single agents. When the agents were combined there was a further reduction in cell viability in both PDX 1 and PDX 2. In line with this reduction in cell viability, there was a large increase in cell death via the apoptotic pathway in the combination treated cell cultures quantified as determined by annexin V/PI and caspase 3 staining. The results for the combination of lovastatin and prochlorperazine were greater than an expected additive effect based on the single agent results, demonstrating a synergistic benefit to their combination.
Example 3 - Concentration Response Combination Studies of prochlorperazine and lovastatin
Materials and Methods Cell culture conditions
Concentration response combination studies were carried out in the PDX 1, 2 and 3 cell models. Cells were cultured using the same protocol as described for the monotherapy studies. At seeding, cells were treated with lovastatin combined with prochlorperazine in a 6x6 concentration matrix of increasing concentrations of both drugs. Cells were cultured for 3 or 7 days; cell viability was quantified using the CellTiter-Glo® luminescence Cell Viability Assay.
Drugs
Prochlorperazine maleate and lovastatin had a purity of >95%. Drugs were tested in triplicate, the top concentration of lovastatin was 20pM, the top concentration of prochlorperazine was 5pM (free-base equivalent).
Data analysis
Cell viability readouts were normalized to DMSO treated controls and a viability matrix was produced. ZIP combination synergy scores were calculated from this matrix using ZIP Synergy Finder ver 2.0 https ://svneravfinder. fimm.fi/ (Ianevski etal, Nucleic Acids Research, 2020, Pages W488-W493). Scores of -10 to 10 indicate an additive combination effect, scores of >10 indicate a synergistic combination effect. Results
The results of the combined treatment of lovastatin and prochlorperazine can be seen in Table 2. There was an additive reduction in cell viability when I prochlorperazine was combined with lovastatin in PDX 1 and PDX 2 after 3 days of treatment, indicated by ZIP scores between -10 and 10. There was a synergistic reduction in cell viability of both PDX 1 and PDX 2 when prochlorperazine was combined with lovastatin indicated by ZIP scores of >10 after 7 days of treatment.
Table 2 - ZIP Synergy scores for combinations of lovastatin and prochlorperazine (Scores of -10 to 10 indicate an additive combination effect, scores of >10 indicate a synergistic combination effect)
Conclusions
Prochlorperazine inhibits the cell viability and increases cell death in neuroblastoma cell lines, and is therefore effective at treating neuroblastoma. The reduction in cell viability can be further enhanced when a combination of prochlorperazine and lovastatin is used. The combination treatment leads to synergistic increases (i.e. greater than the expected additive values) in cell death and reduction in cell viability, and this synergy is quantified by the ZIP synergy scores.
Claims
1. A composition comprising prochlorperazine or a pharmaceutically acceptable salt thereof, for use in the treatment of neuroblastoma.
2. The composition for use according to any preceding claim wherein the subject of the treatment is a moderate or high risk subject, preferably high risk.
3. The composition for use according to any preceding claim, wherein the subject of the treatment or prevention is a human.
4. The composition for use according to any preceding claim, wherein the subject of the treatment is a paediatric patient.
5. The composition for use according to any preceding claim, wherein the pharmaceutically acceptable salt of prochlorperazine is maleate.
6. The composition for use according to any one of claims 1 to 4, wherein the pharmaceutically acceptable salt of prochlorperazine is edisylate.
7. The composition for use according to any one of claims 1 to 4, wherein the pharmaceutically acceptable salt of prochlorperazine is mesylate.
8. The composition for use according to any preceding claim, wherein the composition comprises 1 mg to 40 mg, preferably 5 mg to 35 mg, more preferably 10 mg to 30 mg of prochlorperazine.
9. The composition for use according to any preceding claim, wherein administration is by a dose two times per day.
10. The composition for use according to claim 9, wherein the dose comprises 0.5 mg to 20 mg, preferably 2.5 mg to 17.5 mg, more preferably 5 mg to 15 mg of prochlorperazine.
11. The composition for use according to any of claims 1 to 7, where administration is by a dose three times per day.
12. The composition for use according to claim 11, wherein the dose comprises 0.3 mg to 13 mg, preferably 1.7 mg to 12 mg, more preferably 3 mg to 10 mg of prochlorperazine.
13. The composition for use according to any preceding claim, to be administered orally or intravenously.
14. The composition for use according to any of claims 1 to 12, to be administered by parenteral, transdermal, sublingual, rectal or inhaled administration.
15. The composition for use according to any preceding claim, wherein prochlorperazine is the only active agent in the composition.
16. The composition for use according to any of claims 1 to 14 wherein the composition further comprises lovastatin, or a pharmaceutically acceptable salt thereof.
17. The composition for use according to any of claims 1 to 14 in combination with a second composition comprising lovastatin, or a pharmaceutically acceptable salt thereof, wherein the two compositions are to be administered to a subject simultaneously, separately or sequentially.
18. The composition for use according to either claim 16 or 17, wherein the amount of lovastatin is 1 to 100 mg.
19. A kit comprising :
(i) at least one dose of prochlorperazine, or a pharmaceutically acceptable salt thereof; and
(ii) at least one dose of lovastatin, or a pharmaceutically acceptable salt thereof, for simultaneous, separate or sequential use in the treatment of neuroblastoma.
20. A kit according to claim 19, having any of the additional features of claims 2 to 18.
21. Use of prochlorperazine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment of neuroblastoma.
22. Use according to claim 21, having any of the additional features of claims 2 to 18.
23. A method of treating neuroblastoma comprising administering to a patient a composition comprising prochlorperazine or a pharmaceutically acceptable salt thereof.
24. The method according to claim 23, having any of the additional features of claims 2 to 18.
25. The method according to claims 23 or 24 wherein the method further comprises administering to the patient a second composition comprising lovastatin, or a pharmaceutically acceptable salt thereof, wherein the two compositions are administered simultaneously, separately or sequentially.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB2102373.4A GB202102373D0 (en) | 2021-02-19 | 2021-02-19 | Treatment |
GB2102373.4 | 2021-02-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2022175673A1 true WO2022175673A1 (en) | 2022-08-25 |
Family
ID=75339297
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2022/050443 WO2022175673A1 (en) | 2021-02-19 | 2022-02-18 | Prochlorperazine for use in the treatment of neuroblastoma |
Country Status (2)
Country | Link |
---|---|
GB (1) | GB202102373D0 (en) |
WO (1) | WO2022175673A1 (en) |
-
2021
- 2021-02-19 GB GBGB2102373.4A patent/GB202102373D0/en not_active Ceased
-
2022
- 2022-02-18 WO PCT/GB2022/050443 patent/WO2022175673A1/en active Application Filing
Non-Patent Citations (6)
Title |
---|
BRAEKEVELDT ET AL., INT. J. CANCER, 2015, pages E252 - E261 |
DANIELLE E ARNOLD ET AL: "Lovastatin induces neuronal differentiation and apoptosis of embryonal carcinoma and neuroblastoma cells: enhanced differentiation and apoptosis in combination with dbcAMP", MOLECULAR AND CELLULAR BIOCHEMISTRY, KLUWER ACADEMIC PUBLISHERS, BO, vol. 345, no. 1 - 2, 9 August 2010 (2010-08-09), pages 1 - 11, XP019859147, ISSN: 1573-4919, DOI: 10.1007/S11010-010-0553-Z * |
DE PRETER KATLEEN ET AL: "Meta-mining of Neuroblastoma and Neuroblast Gene Expression Profiles Reveals Candidate Therapeutic Compounds", CLINICAL CANCER RESEARCH, vol. 15, no. 11, 12 May 2009 (2009-05-12), US, pages 3690 - 3696, XP055904057, ISSN: 1078-0432, DOI: 10.1158/1078-0432.CCR-08-2699 * |
IANEVSKI ET AL., NUCLEIC ACIDS RESEARCH, 2020, pages W488 - W493 |
IFRIT GIL-AD ET AL: "Characterization of Phenothiazine-Induced Apoptosis in Neuroblastoma and Glioma Cell Lines", JOURNAL OF MOLECULAR NEUROSCIENCE, BIRKHAEUSER, CAMBRIDGE, MA, US, vol. 22, 1 January 2004 (2004-01-01), pages 189 - 198, XP009092693, ISSN: 0895-8696, DOI: 10.1385/JMN:22:3:189 * |
SOLONIUK D S ET AL: "Lovastatin as an adjunct agent in brain tumor chemotherapy", SURGICAL FORUM, CHICAGO, US, vol. 43, 1 January 1992 (1992-01-01), pages 530 - 532, XP009534459, ISSN: 0071-8041 * |
Also Published As
Publication number | Publication date |
---|---|
GB202102373D0 (en) | 2021-04-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10245240B2 (en) | Treatment of prostate carcinoma | |
US10292962B2 (en) | Pharmaceutical combination comprising metformin and dihydroquercetin and its use for the treatment of cancer | |
CN105873440A (en) | Methods for inhibiting tie2 kinase useful in the treatment of cancer | |
EP2832358A1 (en) | Pharmaceutical kit for use in the treatment of colon and colorectal cancer | |
TW201609094A (en) | Novel methods for treating cancer | |
WO2015172712A1 (en) | Pharmaceutical composition for injection with synergistic effect of vitamin c and antitumour drugs | |
JP2021505571A (en) | Compositions and Methods for Treating Peripheral T-Cell Lymphoma and Cutaneous T-Cell Lymphoma | |
CN112641775A (en) | Application of brucea javanica picrol and analogues thereof in treatment of pituitary adenoma | |
US20120245190A1 (en) | Autophagy inducing compound and the uses thereof | |
US8349902B2 (en) | Pharmaceutical compositions useful for preventing and treating oncological diseases | |
TW201311263A (en) | Wogonin-containing pharmaceutical composition for inhibiting cancer stem cells growth and application thereof | |
US20120252773A1 (en) | Method and composition for inhibiting cell proliferation and angiogenesis | |
WO2022175673A1 (en) | Prochlorperazine for use in the treatment of neuroblastoma | |
EP3880207A1 (en) | Combination of a mcl-1 inhibitor and midostaurin, uses and pharmaceutical compositions thereof | |
WO2022175671A1 (en) | Trifluoperazine for use in the treatment of neurobéastoma | |
WO2022175670A1 (en) | Lovastatin for use in the treatment of neuroblastoma | |
WO2023089328A1 (en) | Nitroxoline for use in the treatment or prevention of a plexiform neurofibroma | |
RU2516027C2 (en) | Combination of anticancer agents | |
CN112587518A (en) | Brucea javanica picrol pharmaceutical composition and application thereof | |
US20230088704A1 (en) | A pharmaceutical combination for the treatment of a cancer | |
US20130172656A1 (en) | Novel use of armillaridin for treating cancer | |
EP4349339A1 (en) | Pharmaceutical composition for treatment of cancer and use thereof | |
TWI406658B (en) | Use of isothiocyanates for treating cancer | |
US20210137945A1 (en) | Method for treating a cancer associated with the activation of galectin-1 | |
TWI607752B (en) | Use of a composition containing 4-acetyl-antroquinonol b for preparing pharmaceutical compositions for inhibiting growth of ovarian cancer cells |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22706885 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 22706885 Country of ref document: EP Kind code of ref document: A1 |