CN112316149A - 一种治疗tp53突变的晚期难治性实体瘤的药物及应用 - Google Patents
一种治疗tp53突变的晚期难治性实体瘤的药物及应用 Download PDFInfo
- Publication number
- CN112316149A CN112316149A CN202011252897.9A CN202011252897A CN112316149A CN 112316149 A CN112316149 A CN 112316149A CN 202011252897 A CN202011252897 A CN 202011252897A CN 112316149 A CN112316149 A CN 112316149A
- Authority
- CN
- China
- Prior art keywords
- medicament
- advanced refractory
- treatment
- treating
- cancer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003814 drug Substances 0.000 title claims abstract description 89
- 108010078814 Tumor Suppressor Protein p53 Proteins 0.000 title claims abstract description 45
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 33
- 102000015098 Tumor Suppressor Protein p53 Human genes 0.000 title description 37
- 229940079593 drug Drugs 0.000 title description 21
- 239000012661 PARP inhibitor Substances 0.000 claims abstract description 27
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 claims abstract description 27
- WPEWQEMJFLWMLV-UHFFFAOYSA-N n-[4-(1-cyanocyclopentyl)phenyl]-2-(pyridin-4-ylmethylamino)pyridine-3-carboxamide Chemical compound C=1C=CN=C(NCC=2C=CN=CC=2)C=1C(=O)NC(C=C1)=CC=C1C1(C#N)CCCC1 WPEWQEMJFLWMLV-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229960003982 apatinib Drugs 0.000 claims abstract description 21
- 239000004037 angiogenesis inhibitor Substances 0.000 claims abstract description 17
- -1 BRCA Proteins 0.000 claims abstract description 8
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 claims abstract 8
- FDLYAMZZIXQODN-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC=2C3=CC=CC=C3C(=O)NN=2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FDLYAMZZIXQODN-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 6
- 229960000572 olaparib Drugs 0.000 claims description 6
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 claims description 5
- 206010060862 Prostate cancer Diseases 0.000 claims description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 5
- 239000003798 L01XE11 - Pazopanib Substances 0.000 claims description 4
- 206010027476 Metastases Diseases 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 101710179684 Poly [ADP-ribose] polymerase Proteins 0.000 claims description 4
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 claims description 4
- 229960000639 pazopanib Drugs 0.000 claims description 4
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 claims description 4
- XXJWYDDUDKYVKI-UHFFFAOYSA-N 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline Chemical compound COC1=CC2=C(OC=3C(=C4C=C(C)NC4=CC=3)F)N=CN=C2C=C1OCCCN1CCCC1 XXJWYDDUDKYVKI-UHFFFAOYSA-N 0.000 claims description 3
- MDOJTZQKHMAPBK-UHFFFAOYSA-N 4-iodo-3-nitrobenzamide Chemical compound NC(=O)C1=CC=C(I)C([N+]([O-])=O)=C1 MDOJTZQKHMAPBK-UHFFFAOYSA-N 0.000 claims description 3
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010014733 Endometrial cancer Diseases 0.000 claims description 3
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 3
- 239000002147 L01XE04 - Sunitinib Substances 0.000 claims description 3
- 239000005511 L01XE05 - Sorafenib Substances 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
- 229960003005 axitinib Drugs 0.000 claims description 3
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 claims description 3
- 229960000397 bevacizumab Drugs 0.000 claims description 3
- 229960002412 cediranib Drugs 0.000 claims description 3
- HWGQMRYQVZSGDQ-HZPDHXFCSA-N chembl3137320 Chemical compound CN1N=CN=C1[C@H]([C@H](N1)C=2C=CC(F)=CC=2)C2=NNC(=O)C3=C2C1=CC(F)=C3 HWGQMRYQVZSGDQ-HZPDHXFCSA-N 0.000 claims description 3
- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 229950002133 iniparib Drugs 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 229960003787 sorafenib Drugs 0.000 claims description 3
- 201000011549 stomach cancer Diseases 0.000 claims description 3
- 229960001796 sunitinib Drugs 0.000 claims description 3
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 claims description 3
- 229950004550 talazoparib Drugs 0.000 claims description 3
- 229950011257 veliparib Drugs 0.000 claims description 3
- JNAHVYVRKWKWKQ-CYBMUJFWSA-N veliparib Chemical compound N=1C2=CC=CC(C(N)=O)=C2NC=1[C@@]1(C)CCCN1 JNAHVYVRKWKWKQ-CYBMUJFWSA-N 0.000 claims description 3
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 206010038389 Renal cancer Diseases 0.000 claims description 2
- 206010039491 Sarcoma Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 201000010982 kidney cancer Diseases 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 3
- 239000005536 L01XE08 - Nilotinib Substances 0.000 claims 1
- 229960001346 nilotinib Drugs 0.000 claims 1
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 22
- 108090000623 proteins and genes Proteins 0.000 abstract description 9
- 230000003527 anti-angiogenesis Effects 0.000 abstract description 8
- 208000037844 advanced solid tumor Diseases 0.000 abstract description 7
- 230000001093 anti-cancer Effects 0.000 abstract description 4
- 230000034431 double-strand break repair via homologous recombination Effects 0.000 abstract description 4
- 206010021143 Hypoxia Diseases 0.000 abstract description 3
- 102000002490 Rad51 Recombinase Human genes 0.000 abstract description 3
- 108010068097 Rad51 Recombinase Proteins 0.000 abstract description 3
- 230000007954 hypoxia Effects 0.000 abstract description 2
- 230000035772 mutation Effects 0.000 description 20
- 210000004881 tumor cell Anatomy 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 7
- 238000001574 biopsy Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 4
- BKWJAKQVGHWELA-UHFFFAOYSA-N 1-[6-(2-hydroxypropan-2-yl)-2-pyridinyl]-6-[4-(4-methyl-1-piperazinyl)anilino]-2-prop-2-enyl-3-pyrazolo[3,4-d]pyrimidinone Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC=C2C(=O)N(CC=C)N(C=3N=C(C=CC=3)C(C)(C)O)C2=N1 BKWJAKQVGHWELA-UHFFFAOYSA-N 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 229950009557 adavosertib Drugs 0.000 description 3
- 230000033115 angiogenesis Effects 0.000 description 3
- 190000008236 carboplatin Chemical compound 0.000 description 3
- 229960004562 carboplatin Drugs 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000009401 metastasis Effects 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 230000008439 repair process Effects 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 2
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000004777 loss-of-function mutation Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- HMABYWSNWIZPAG-UHFFFAOYSA-N rucaparib Chemical compound C1=CC(CNC)=CC=C1C(N1)=C2CCNC(=O)C3=C2C1=CC(F)=C3 HMABYWSNWIZPAG-UHFFFAOYSA-N 0.000 description 2
- 229950004707 rucaparib Drugs 0.000 description 2
- 238000011729 BALB/c nude mouse Methods 0.000 description 1
- 102000036365 BRCA1 Human genes 0.000 description 1
- 108700020463 BRCA1 Proteins 0.000 description 1
- 101150072950 BRCA1 gene Proteins 0.000 description 1
- 102000052609 BRCA2 Human genes 0.000 description 1
- 108700020462 BRCA2 Proteins 0.000 description 1
- 101150008921 Brca2 gene Proteins 0.000 description 1
- 101100407084 Caenorhabditis elegans parp-2 gene Proteins 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 230000005971 DNA damage repair Effects 0.000 description 1
- 230000033616 DNA repair Effects 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 206010040914 Skin reaction Diseases 0.000 description 1
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 229940124304 VEGF/VEGFR inhibitor Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000011122 anti-angiogenic therapy Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000006801 homologous recombination Effects 0.000 description 1
- 238000002744 homologous recombination Methods 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000036438 mutation frequency Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 231100000430 skin reaction Toxicity 0.000 description 1
- 230000035483 skin reaction Effects 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明属于精准医学技术领域,公开了一种治疗TP53突变的晚期难治性实体瘤的药物及应用,所述治疗TP53突变的晚期难治性实体瘤的药物为阿帕替尼和奥拉帕利。本发明利用抗血管生成药物联合PARP抑制剂用于治疗TP53突变的晚期实体瘤,取得了神奇的疗效。抗血管生成药物联合PARP抑制剂已经在临床前研究里显示出一定的抗癌疗效。抗血管生成药物能够下调如BRCA、RAD51等同源重组修复相关基因,同时能够使细胞处于乏氧状态,能增强PARP抑制剂的治疗效果。
Description
技术领域
本发明属于精准医学技术领域,尤其涉及一种治疗TP53突变的晚期难治性实体瘤的药物及应用。
背景技术
目前,最接近的现有技术:在人类肿瘤中,TP53突变是最为常见的抑癌基因突变,突变频率在10%到96%之间。TP53有害突变导致细胞周期阻滞和DNA损阿伤修复功能受损,导致靶基因的过表达及基因组不稳定,从而促进肿瘤的发生发展。然而,目前还没有有效的方法来治疗TP53突变的肿瘤。因此,迫切需要一种能够靶向TP53突变肿瘤的有效治疗策略,以改善该类患者的病情并延长生存期。血管生成促进癌细胞的生长和扩散,其在肿瘤形成和发展中发挥着重要的作用。而血管内皮生长因子(VEGF)激活血管内皮生长因子受体(VEGFR)是血管形成信号通路里的关键一步。通过阻断该通路来治疗肿瘤已经取得了一定的疗效,如帕唑帕尼治疗肾细胞癌、阿帕替尼治疗胃癌等都已经被批准上市。目前常用的抗血管生成药物包括帕唑帕尼、索拉菲尼、舒尼替尼、阿帕替尼、阿西替尼、贝伐单抗等。因为缺少特异性的靶点,抗血管生成药物也只能短暂的延长患者的生存期。已有一些研究表明,TP53突变的患者应用抗VEGF/VEGFR抑制剂能获得更佳的治疗反应,TP53突变可能是其有效的治疗靶点。
PARP抑制剂如奥拉帕利已经批准用于治疗BRCA突变晚期卵巢癌和乳腺癌。PARPs是一类蛋白家族,它们能结合到损伤的DNA单链上,招募DNA修复蛋白来促进DNA单链的损伤修复,人类中常见的PARP家族蛋白为PARP1和PARP2。PARP抑制剂的作用机理主要是合成致死原理,通过抑制PARP的活性,使DNA单链的修复难以完成进而导致双链损伤,DNA双链损伤在人体主要通过同源重组机制来修复。在那些伴有BRCA1、BRCA2等突变的肿瘤中,这种同源重组修复机制是有缺陷的,所以当全部两条修复通路都无效时,细胞便会死亡。因为人体正常的细胞不会像肿瘤细胞那样频繁分裂,所以PARP抑制剂能对肿瘤细胞发挥更大的杀伤作用。目前常用的PARP抑制剂包括奥拉帕利(olaparib)、尼拉帕尼(niraparib)、iniparib、talazoparib、rucaparib、veliparib等。抗血管生成治疗联合PARP抑制剂已经在临床前研究里显示出一定的抗癌疗效。抗血管生成药物能够下调如BRCA、RAD51等同源重组修复相关基因,同时能够使细胞处于乏氧状态,这都能增强PARP抑制剂的治疗效果,单独使用PARP抑制剂疗效不佳,而抗血管生成药物能够增强PARP抑制剂的治疗效果。Joyce F Liu和它的同事研究发现抗血管生成药物西地尼布联合PARP抑制剂奥拉帕利在复发性卵巢癌中的抗癌效果远优于奥拉帕利单药治疗。在于患者都需要进行基因检测以检出TP53突变,目前基因检测技术还需要进一步规范化且该检测价格比较高;另外,靶向药物价格也比较高,随着靶向药逐渐纳入医保报销,这个问题应该能得到一定解决。
综上所述,现有技术存在的问题是:目前常用的抗血管生成药物包括帕唑帕尼、索拉菲尼、舒尼替尼、阿帕替尼、阿西替尼、贝伐单抗等,缺少特异性的靶点。
解决上述技术问题的难度:解决抗血管生成药物缺少特异性靶点的问题还需要更多细胞生物学实验和动物实验探索,这个可能还需要很长的时间,而且探索之后也不一定顺利,本发明可能要另辟蹊径。
解决上述技术问题的意义:本发明通过在使用抗血管生成药物的基础上联用PARP抑制剂使得TP53突变的实体瘤患者肿瘤显著缩小,这是一种新的思路。结果无疑对肿瘤患者的治疗很有意义,延长了肿瘤患者的生命。
发明内容
针对现有技术存在的问题,本发明提供了一种治疗TP53突变的晚期难治性实体瘤的药物及应用。
本发明是这样实现的,一种治疗TP53突变的晚期难治性实体瘤的药物,其特征在于,所述药物为抗血管生成药物联合PARP抑制剂组合。
所述抗血管生成药物的分子式为C25H27N5O4S:
所述PARP抑制剂的分子式为C24H23FN4O3:
进一步,所述PARP抑制剂包括奥拉帕利(olaparib)、尼拉帕尼(niraparib)、iniparib、talazoparib、rucaparib、veliparib。
进一步,所述治疗TP53突变的晚期难治性实体瘤的药物,所述治疗TP53突变的晚期难治性实体瘤的药物为阿帕替尼和奥拉帕利。
本发明的另一目的在于提供一种治疗TP53突变的晚期难治性实体瘤的药物的使用方法,阿帕替尼250mg,每日1次,奥拉帕利150mg,每日2次。
本发明的另一目的在于提供一种利用上述药物得到的治疗晚期难治性前列腺癌的药物。
本发明的另一目的在于提供一种利用上述药物得到的治疗晚期难治性子宫内膜癌的药物。
本发明的另一目的在于提供一种利用上述药物得到的治疗晚期难治性胰腺癌的药物。
本发明的另一目的在于提供一种利用上述药物得到的治疗晚期难治性肺癌的药物。
本发明的另一目的在于提供一种利用上述药物得到的治疗晚期难治性卵巢癌的药物。
本发明的另一目的在于提供一种利用上述药物得到的治疗晚期难治性肾癌的药物。
本发明的另一目的在于提供一种利用上述药物得到的治疗晚期难治性膀胱癌的药物。
本发明的另一目的在于提供一种利用上述药物得到的治疗晚期难治性结直肠癌的药物。
本发明的另一目的在于提供一种利用上述药物得到的治疗晚期难治性胃癌的药物。
本发明的另一目的在于提供一种利用上述药物得到的治疗晚期难治性乳腺癌的药物。
本发明的另一目的在于提供一种利用上述药物得到的治疗晚期难治性肉瘤的药物。
本发明的另一目的在于提供一种利用上述药物得到的治疗晚期难治性原发灶未明的转移瘤的药物。
综上所述,本发明的优点及积极效果为:
正如背景技术里提到的,TP53突变的晚期实体瘤恶性程度高,现有技术无法有效治疗,这更突显本发明新方法的实用性和创造性。我们认为目前一些治疗肿瘤的药物没有做到精准定位病人,可能阿帕替尼联合奥拉帕利在非TP53突变的肿瘤患者中疗效并不好,正是因为找准了TP53突变这一治疗靶点,才体现出了疗效,这也是精准医学的魅力所在。
本发明利用抗血管生成药物联合PARP抑制剂用于治疗TP53突变的晚期实体瘤,取得了神奇的疗效。抗血管生成药物联合PARP抑制剂已经在临床前研究里显示出一定的抗癌疗效。抗血管生成药物能够下调如BRCA、RAD51等同源重组修复相关基因,同时能够使细胞处于乏氧状态,能增强PARP抑制剂的治疗效果。
本发明以抗血管生成药物阿帕替尼联合PARP抑制剂奥拉帕利治疗TP53突变的晚期实体瘤,目前国内外尚未有该技术方案以论文或专利的形式公开发表,且该技术方案疗效得到了临床验证。TP53不同突变状态可以预测抗血管生成药物、PARP抑制剂或两者组合治疗的疗效,TP53错义突变的患者疗效显著优于TP53功能缺失突变的患者。
附图说明
图1-图5是本发明实施例提供的奥拉帕利联合阿帕替尼组对肿瘤细胞抑制作用效果示意图。
图6是本发明实施例提供的干预和评价指标示意图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
下面结合附图对本发明的应用原理作详细的描述。
本发明实施例提供的治疗TP53突变的晚期难治性实体瘤的药物为阿帕替尼和奥拉帕利。
服用阿帕替尼和奥拉帕利时,均为口服用药;由于不同患者耐受性不同,一般其实服用最低有效剂量,如阿帕替尼250mg,每日1次,奥拉帕利150mg,每日2次。
抗血管生成药物的分子式为C25H27N5O4S:
PARP抑制剂的分子式为C24H23FN4O3:
下面结合具体临床实施例对本发明的应用效果作详细的描述。
1、目前,入组了39例TP53突变的晚期难治性实体瘤(8例患者处于肿瘤终末阶段,ECOG评分3-4分),涉及11种不同的癌肿。应用奥拉帕利150mg bid联合阿帕替尼250mg qd口服治疗,连续服用直至疾病进展或不可耐受的毒性。结果显示总体客观缓解率(ORR)、疾病控制率(DCR)和中位无进展时间(PFS)分别是33.3%、82.0%和5个月。其中TP53错义突变的患者疗效显著优于TP53功能缺失突变的患者,ORR和PFS分别是42.3%vs 15.4%和6个月vs3个月。中位总生存期(OS)尚未达到,该联合治疗方案不良反应轻微,最常见的不良反应为疲乏,高血压和手足皮肤反应,没有治疗相关的死亡病例。总体而言,PARP抑制剂(奥拉帕利等)联合抗血管生成药物(如阿帕替尼)在TP53突变的晚期实体瘤患者的治疗中展示了显著的疗效和良好的安全性,尤其在TP53错义突变的亚组人群中效果更好!
表1为TP53突变的晚期实体瘤患者接受PARP抑制剂联合抗血管生成药物与接受Weel抑制剂AZD1775联合卡铂治疗的疗效对比。可见本发明的方案显著优于现有技术。
表1 PARP抑制剂联合抗血管生成药物与AZD1775联合卡铂治疗TP53突变的晚期实体瘤疗效对比
奥拉帕尼联合阿帕替尼 | AZD1775联合卡铂 | |
客观缓解率(ORR) | 33.3% | 10% |
疾病控制率(DCR) | 82.0% | 53% |
2、进行miniPDX模型验证结果病例说明;
miniPDX模型是一种动物实验,是采用特殊方法将原代人源肿瘤细胞移植在免疫缺陷小鼠身上后建立的一种药敏测试模型,通过该模型能够快速地对多种药物及药物组合方案进行药物敏感性测试研究,筛选出最优的个体化用药方案,为患者的临床用药选择提供科学依据。
具体实验步骤如下:
①采集患者组织样本,体外消化成单细胞悬液,过滤去除组织块及细胞团块,去除细胞碎片。
②重悬肿瘤细胞,调整细胞浓度,灌装至Mini PDX评价系统装置。
③接种至实验小鼠(BALB/c-nude mice),按预设好实验方案分组给药。
④实验进行7天,实验结束后取出评价装置,体外ATP方法检测肿瘤细胞活性。
图1至图5为部分实验结果展示,显示出该联合方案优秀的抗肿瘤细胞增殖能力。
如图1所示,患者A,晚期难治性前列腺癌,TP53突变阳性,取肝脏转移灶活检组织行miniPDX模型构建,奥拉帕利联合阿帕替尼组对肿瘤细胞抑制作用最强。
如图2所示,患者B,晚期难治性前列腺癌,TP53突变阳性,取肺转移灶活检组织行miniPDX模型构建,奥拉帕利联合阿帕替尼组对肿瘤细胞抑制作用最强。
如图3所示,患者C,晚期难治性前列腺癌,TP53突变阳性,取前列腺活检组织行miniPDX模型构建,奥拉帕利联合阿帕替尼组对肿瘤细胞抑制作用最强。
如图4所示,患者D,晚期难治性子宫内膜癌,TP53突变阳性,取肿物活检组织行miniPDX模型构建,奥拉帕利联合阿帕替尼组对肿瘤细胞抑制作用最强。
如图5所示,患者E,晚期难治性胰腺癌,TP53突变阳性,取肿物活检组织行miniPDX模型构建,奥拉帕利联合阿帕替尼组对肿瘤细胞抑制作用最强。
上述患者在miniPDX建模药敏试验的指导下,均发现抗血管生成药物(阿帕替尼)联合PARP抑制剂(奥拉帕利)对肿瘤细胞增殖抑制作用最强,临床使用这两种药物结合均达到良好的疗效,充分证明了这两种药物联合治疗TP53突变的晚期难治性实体瘤的可行性。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (16)
2.如权利要求1所述的治疗TP53突变的晚期难治性实体瘤的药物,其特征在于,所述PARP抑制剂包括奥拉帕利olaparib、尼拉帕利niraparib、iniparib、talazoparib、rucaparib、veliparib;所述抗血管生成药物包括阿帕替尼、帕唑帕尼、西地尼布、索拉菲尼、舒尼替尼、阿西替尼、贝伐单抗和安罗替尼。
3.如权利要求1所述治疗TP53突变的晚期难治性实体瘤的药物,其特征在于,所述治疗TP53突变的晚期难治性实体瘤的药物为阿帕替尼和奥拉帕利的组合;也可以是奥拉帕尼联合西地尼布、奥拉帕尼联合安罗替尼或尼拉帕尼联合安罗替尼。
4.一种治疗TP53突变的晚期难治性实体瘤的药物的使用方法,其特征在于,阿帕替尼250mg,每日1次,奥拉帕利150mg,每日2次。
5.一种利用权利要求1药物得到的治疗晚期难治性前列腺癌的药物。
6.一种利用权利要求1药物得到的治疗晚期难治性子宫内膜癌的药物。
7.一种利用权利要求1药物得到的治疗晚期难治性胰腺癌的药物。
8.一种利用权利要求1药物得到的治疗晚期难治性肺癌的药物。
9.一种利用权利要求1药物得到的治疗晚期难治性卵巢癌的药物。
10.一种利用权利要求1药物得到的治疗晚期难治性肾癌的药物。
11.一种利用权利要求1药物得到的治疗晚期难治性膀胱癌的药物。
12.一种利用权利要求1药物得到的治疗晚期难治性结直肠癌的药物。
13.一种利用权利要求1药物得到的治疗晚期难治性胃癌的药物。
14.一种利用权利要求1药物得到的治疗晚期难治性乳腺癌的药物。
15.一种利用权利要求1药物得到的治疗晚期难治性肉瘤的药物。
16.一种利用权利要求1药物得到的治疗晚期难治性原发灶未明的转移瘤的药物。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202011252897.9A CN112316149A (zh) | 2020-11-11 | 2020-11-11 | 一种治疗tp53突变的晚期难治性实体瘤的药物及应用 |
PCT/CN2021/129759 WO2022100608A1 (zh) | 2020-11-11 | 2021-11-10 | 一种治疗tp53突变的晚期难治性实体瘤的药物及应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202011252897.9A CN112316149A (zh) | 2020-11-11 | 2020-11-11 | 一种治疗tp53突变的晚期难治性实体瘤的药物及应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN112316149A true CN112316149A (zh) | 2021-02-05 |
Family
ID=74317778
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202011252897.9A Pending CN112316149A (zh) | 2020-11-11 | 2020-11-11 | 一种治疗tp53突变的晚期难治性实体瘤的药物及应用 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN112316149A (zh) |
WO (1) | WO2022100608A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022100608A1 (zh) * | 2020-11-11 | 2022-05-19 | 王海涛 | 一种治疗tp53突变的晚期难治性实体瘤的药物及应用 |
CN115105539A (zh) * | 2022-08-01 | 2022-09-27 | 大连医科大学附属第二医院 | 一种parp抑制剂联合石见穿治疗乳腺癌及药物组合 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108778336A (zh) * | 2016-12-01 | 2018-11-09 | 江苏恒瑞医药股份有限公司 | 一种vegfr抑制剂与parp抑制剂联合在制备治疗胃癌的药物中的用途 |
CN111182923A (zh) * | 2017-10-06 | 2020-05-19 | 特沙诺有限公司 | 组合疗法及其用途 |
CN111643503A (zh) * | 2019-03-04 | 2020-09-11 | 正大天晴药业集团股份有限公司 | 用于治疗非小细胞肺癌的喹啉衍生物 |
WO2020211860A1 (zh) * | 2019-04-19 | 2020-10-22 | 正大天晴药业集团股份有限公司 | 用于治疗尤因肉瘤的喹啉类化合物或其药学上可接受的盐 |
CN111840289A (zh) * | 2019-04-28 | 2020-10-30 | 正大天晴药业集团股份有限公司 | 用于治疗骨巨细胞瘤的喹啉类化合物或其药学上可接受的盐 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MX2010005221A (es) * | 2007-11-12 | 2010-09-28 | Bipar Sciences Inc | Tratamiento de cancer de utero y cancer de ovario con un inhibidor de parp solo o en combinacion con agentes antitumorales. |
CN110893189A (zh) * | 2018-09-12 | 2020-03-20 | 江苏恒瑞医药股份有限公司 | 阿帕替尼与依托泊苷联合在制备治疗肺癌的药物中的用途 |
CN111110676A (zh) * | 2020-03-07 | 2020-05-08 | 天津医科大学总医院 | 阿帕替尼及联合cci-779在制备肺癌药物中的应用 |
CN112316149A (zh) * | 2020-11-11 | 2021-02-05 | 王海涛 | 一种治疗tp53突变的晚期难治性实体瘤的药物及应用 |
-
2020
- 2020-11-11 CN CN202011252897.9A patent/CN112316149A/zh active Pending
-
2021
- 2021-11-10 WO PCT/CN2021/129759 patent/WO2022100608A1/zh active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108778336A (zh) * | 2016-12-01 | 2018-11-09 | 江苏恒瑞医药股份有限公司 | 一种vegfr抑制剂与parp抑制剂联合在制备治疗胃癌的药物中的用途 |
CN111182923A (zh) * | 2017-10-06 | 2020-05-19 | 特沙诺有限公司 | 组合疗法及其用途 |
CN111643503A (zh) * | 2019-03-04 | 2020-09-11 | 正大天晴药业集团股份有限公司 | 用于治疗非小细胞肺癌的喹啉衍生物 |
WO2020211860A1 (zh) * | 2019-04-19 | 2020-10-22 | 正大天晴药业集团股份有限公司 | 用于治疗尤因肉瘤的喹啉类化合物或其药学上可接受的盐 |
CN111840289A (zh) * | 2019-04-28 | 2020-10-30 | 正大天晴药业集团股份有限公司 | 用于治疗骨巨细胞瘤的喹啉类化合物或其药学上可接受的盐 |
Non-Patent Citations (2)
Title |
---|
FEIFEI ZHANG等: "用于预测癌症患者临床治疗方案的小鼠mini人源肿瘤异种移植模型的建立", 《癌症》 * |
查雪丽: "93例复发性卵巢癌临床特点及预后相关因素分析", 《中国优秀硕士学位论文全文数据库》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022100608A1 (zh) * | 2020-11-11 | 2022-05-19 | 王海涛 | 一种治疗tp53突变的晚期难治性实体瘤的药物及应用 |
CN115105539A (zh) * | 2022-08-01 | 2022-09-27 | 大连医科大学附属第二医院 | 一种parp抑制剂联合石见穿治疗乳腺癌及药物组合 |
Also Published As
Publication number | Publication date |
---|---|
WO2022100608A1 (zh) | 2022-05-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Kim et al. | Perspective of mesenchymal transformation in glioblastoma | |
Beatty et al. | The biological underpinnings of therapeutic resistance in pancreatic cancer | |
Moser et al. | The mechanisms of action of Tumor Treating Fields | |
Andrikopoulou et al. | Clinical perspectives of BET inhibition in ovarian cancer | |
WO2022100608A1 (zh) | 一种治疗tp53突变的晚期难治性实体瘤的药物及应用 | |
Bryant et al. | Targeting hypoxia in the treatment of small cell lung cancer | |
Guan et al. | Blood–Brain barrier, cell junctions, and tumor microenvironment in brain metastases, the biological prospects and dilemma in therapies | |
CN109364079B (zh) | 塔拉帕尼在制备治疗或者预防肝炎病毒相关疾病药物中的用途 | |
Karapanou et al. | Advanced RAI-refractory thyroid cancer: an update on treatment perspectives | |
Caragher et al. | Radiotherapy and glioma stem cells: searching for chinks in cellular armor | |
Xue et al. | Therapeutic evaluation of palbociclib and its compatibility with other chemotherapies for primary and recurrent nasopharyngeal carcinoma | |
Duan et al. | BRD4: New hope in the battle against glioblastoma | |
CN106389437A (zh) | 低剂量西地那非作为抗肿瘤药物的应用 | |
US20220323450A1 (en) | Methods and compositions for treating neuroblastoma in a juvenile mammalian body | |
US11541061B2 (en) | Neuroblastoma treatment with taurolidine hydrolysis products | |
Dong et al. | Phase 1 Study of the Selective c-MET Inhibitor, HS-10241, in Patients With Advanced Solid Tumors | |
Chen et al. | Synthetic lethality is a novel and potential paradigm for precision medicine in advanced hepatocellular carcinoma | |
Jiang et al. | Combined anti-PD1 immunotherapy for patient with advanced pancreatic cancer: A case report | |
Zhou et al. | 61 Functional characterization of ribosomal RNA methyltransferase NSUN5 in glioblastoma | |
Zhu et al. | [Retracted] Apatinib plus Radiotherapy on the Expression of CEA and VEGF in Advanced Oligometastatic Non‐Small‐Cell Lung Cancer | |
Yu et al. | Radiotherapy in the preoperative neoadjuvant treatment of locally advanced rectal cancer | |
Deng et al. | A bibliometric analysis of the application of the PI3K-AKT-mTOR signaling pathway in cancer | |
Collinson et al. | PRISM: A randomised phase II trial of nivolumab in combination with alternatively scheduled ipilimumab in first-line treatment of patients with advanced or metastatic renal cell carcinoma | |
Huang et al. | LONG NON-CODING RNA, MEG3, SUPPRESSES BLADDER CANCER INVASION BY COMPETITIVELY BINDING MIR-27A AND PROMOTING PROTEIN TRANSLATION OF PHLPP2 TUMOR SUPPRESSOR: MP98-08 | |
Gandia et al. | Some essential issues in cancer biology |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
RJ01 | Rejection of invention patent application after publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20210205 |