WO2022100608A1 - Drug for treating advanced refractory solid tumor having tp53 mutation and application thereof - Google Patents
Drug for treating advanced refractory solid tumor having tp53 mutation and application thereof Download PDFInfo
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- WO2022100608A1 WO2022100608A1 PCT/CN2021/129759 CN2021129759W WO2022100608A1 WO 2022100608 A1 WO2022100608 A1 WO 2022100608A1 CN 2021129759 W CN2021129759 W CN 2021129759W WO 2022100608 A1 WO2022100608 A1 WO 2022100608A1
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- A—HUMAN NECESSITIES
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- 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
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- 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
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Definitions
- the invention belongs to the technical field of precision medicine, and in particular relates to a medicine and application for treating advanced refractory solid tumors with TP53 mutation.
- TP53 mutations are the most common tumor suppressor gene mutations in human tumors, with mutation frequencies ranging from 10% to 96%. Detrimental mutations in TP53 lead to cell cycle arrest and impaired DNA damage repair function, resulting in overexpression of target genes and genomic instability, thereby promoting tumorigenesis and progression.
- an effective therapeutic strategy that can target TP53-mutated tumors is urgently needed to improve the condition and prolong survival of these patients.
- Angiogenesis promotes the growth and spread of cancer cells and plays an important role in tumor formation and progression.
- VEGF Vascular endothelial growth factor activation of vascular endothelial growth factor receptor
- VEGFR vascular endothelial growth factor receptor
- Blocking this pathway to treat tumors has achieved certain curative effects.
- pazopanib in the treatment of renal cell carcinoma and apatinib in the treatment of gastric cancer have been approved for marketing.
- anti-angiogenic drugs include pazopanib, sorafenib, sunitinib, apatinib, axitinib, and bevacizumab. Because of the lack of specific targets, antiangiogenic drugs can only temporarily prolong the survival of patients.
- TP53 mutation can obtain better therapeutic response with anti-VEGF/VEGFR inhibitors, and TP53 mutation may be an effective therapeutic target.
- PARP inhibitors such as olaparib are already approved for the treatment of BRCA-mutated advanced ovarian and breast cancer.
- PARPs are a family of proteins that can bind to damaged DNA single strands and recruit DNA repair proteins to promote DNA single strand damage repair.
- Common PARP family proteins in humans are PARP1 and PARP2.
- the mechanism of action of PARP inhibitors is mainly based on the principle of synthetic lethality. By inhibiting the activity of PARP, the repair of DNA single-strand is difficult to complete, which leads to double-strand damage. DNA double-strand damage is mainly repaired by homologous recombination in the human body.
- PARP inhibitors can exert a greater killing effect on tumor cells.
- PARP inhibitors include olaparib, niraparib, iniparib, talazoparib, rucaparib, veliparib and the like. Antiangiogenic therapy combined with PARP inhibitors has shown certain anticancer efficacy in preclinical studies.
- Anti-angiogenic drugs can downregulate genes related to homologous recombination repair such as BRCA and RAD51, and at the same time can make cells in a hypoxic state, which can enhance the therapeutic effect of PARP inhibitors. Generated drugs can enhance the therapeutic effect of PARP inhibitors.
- Joyce F Liu and colleagues found that the anti-angiogenic drug cediranib combined with the PARP inhibitor olaparib was far more effective than olaparib monotherapy in recurrent ovarian cancer. All patients need to undergo genetic testing to detect TP53 mutations. At present, the genetic testing technology needs to be further standardized and the price of the test is relatively high; in addition, the price of targeted drugs is also relatively high. As targeted drugs are gradually included in medical insurance reimbursement, this problem Should be able to get some solution.
- the problems existing in the prior art are: the currently commonly used anti-angiogenic drugs include pazopanib, sorafenib, sunitinib, nigra, axitinib, bevacizumab, etc. specific target.
- the present invention provides a medicine and application for treating advanced refractory solid tumors with TP53 mutation.
- the present invention is achieved in this way, a drug for the treatment of advanced refractory solid tumors with TP53 mutation, characterized in that the drug is a combination of an anti-angiogenesis drug and a PARP inhibitor.
- the molecular formula of the anti-angiogenic drug is C 25 H 27 N 5 O 4 S:
- the molecular formula of the PARP inhibitor is C 24 H 23 FN 4 O 3 :
- the PARP inhibitors include olaparib, niraparib, iniparib, talazoparib, rucaparib, and veliparib.
- the drugs for treating advanced refractory solid tumors with TP53 mutation are apatinib and olaparib.
- Another object of the present invention is to provide a method of using a drug for the treatment of advanced refractory solid tumors with TP53 mutation, apatinib 250 mg once a day, and olaparib 150 mg twice a day.
- Another object of the present invention is to provide a medicament for the treatment of advanced refractory prostate cancer obtained by using the above medicament.
- Another object of the present invention is to provide a medicament for the treatment of advanced refractory endometrial cancer obtained by using the above medicament.
- Another object of the present invention is to provide a medicament for the treatment of advanced refractory pancreatic cancer obtained by using the above medicament.
- Another object of the present invention is to provide a medicament for the treatment of advanced refractory lung cancer obtained by using the above medicament.
- Another object of the present invention is to provide a medicament for the treatment of advanced refractory ovarian cancer obtained by using the above medicament.
- Another object of the present invention is to provide a medicament for the treatment of advanced refractory renal cancer obtained by using the above medicament.
- Another object of the present invention is to provide a medicament for the treatment of advanced refractory bladder cancer obtained by using the above medicament.
- Another object of the present invention is to provide a medicament for the treatment of advanced refractory colorectal cancer obtained by using the above medicament.
- Another object of the present invention is to provide a medicament for the treatment of advanced refractory breast cancer obtained by using the above medicament.
- Another object of the present invention is to provide a medicament for the treatment of advanced refractory sarcoma obtained by using the above medicament.
- Another object of the present invention is to provide a medicament for the treatment of advanced refractory metastases with unknown primary tumor obtained by using the above medicament.
- the tumor of the TP53-mutated solid tumor patient can be significantly reduced by using an anti-angiogenesis drug in combination with a PARP inhibitor, which is a new idea.
- the results are undoubtedly meaningful for the treatment of tumor patients and prolong the life of tumor patients.
- the present invention utilizes anti-angiogenesis drugs combined with PARP inhibitors to treat advanced solid tumors with TP53 mutation, and achieves a spontaneous curative effect.
- Antiangiogenic drugs combined with PARP inhibitors have shown certain anticancer efficacy in preclinical studies.
- Anti-angiogenic drugs can down-regulate genes related to homologous recombination repair such as BRCA and RAD51, and at the same time can make cells in a hypoxic state, which can enhance the therapeutic effect of PARP inhibitors.
- the anti-angiogenic drug apatinib combined with the PARP inhibitor olaparib is used to treat the advanced solid tumor with TP53 mutation.
- TP53 mutation no such technical solution has been published in the form of papers or patents at home and abroad, and the efficacy of the technical solution has been obtained. clinically validated.
- Different mutational status of TP53 can predict the efficacy of anti-angiogenic drugs, PARP inhibitors or the combination of the two, and the efficacy of patients with TP53 missense mutations is significantly better than that of patients with TP53 loss-of-function mutations.
- FIG. 1 is a schematic diagram of the inhibitory effect of olaparib combined with apatinib group on patient A tumor cells provided in the embodiment of the present invention
- FIG. 2 is a schematic diagram of the inhibitory effect of olaparib combined with apatinib group on patient B tumor cells provided in the embodiment of the present invention
- FIG. 3 is a schematic diagram of the inhibitory effect of olaparib combined with apatinib group on patient C tumor cells provided in the embodiment of the present invention
- FIG. 4 is a schematic diagram of the inhibitory effect of olaparib combined with apatinib group on patient D tumor cells provided in the embodiment of the present invention
- Figure 5 is a schematic diagram of the inhibitory effect of olaparib combined with apatinib group on patient E tumor cells provided in the embodiment of the present invention
- FIG. 6 is a schematic diagram of intervention and evaluation indicators provided by an embodiment of the present invention.
- the drugs for the treatment of advanced refractory solid tumors with TP53 mutation provided in the embodiments of the present invention are apatinib and olaparib.
- apatinib and olaparib both are taken orally; due to the different tolerance of different patients, the lowest effective dose is generally taken, such as apatinib 250mg, once a day, olaparib 150mg, 2 times a day.
- the molecular formula of the anti-angiogenic drug is C 25 H 27 N 5 O 4 S:
- the molecular formula of the PARP inhibitor is C 24 H 23 FN 4 O 3 :
- Table 1 compares the efficacy of PARP inhibitor combined with antiangiogenic drugs and Weel inhibitor AZD1775 combined with carboplatin in patients with TP53-mutated advanced solid tumors. It can be seen that the solution of the present invention is significantly better than the prior art.
- Olaparib combined with apatinib AZD1775 combined with carboplatin Objective Response Rate (ORR) 33.3% 10% Disease Control Rate (DCR) 82.0% 53%
- the miniPDX model is an animal experiment. It is a drug susceptibility test model established by transplanting primary human tumor cells into immunodeficient mice using a special method. Conduct drug sensitivity test research, screen out the optimal individualized drug regimen, and provide a scientific basis for patients' clinical drug selection.
- the experiment was carried out for 7 days. After the experiment, the evaluation device was taken out, and the activity of tumor cells was detected by in vitro ATP method.
- Figures 1 to 5 are partial experimental results showing that the combined regimen has excellent anti-tumor cell proliferation ability.
- patient A advanced refractory prostate cancer, positive for TP53 mutation, took liver metastases biopsy tissue for miniPDX model construction, and the olaparib combined with apatinib group had the strongest inhibitory effect on tumor cells.
- patient B advanced refractory prostate cancer, positive for TP53 mutation, took the biopsy tissue of lung metastases to construct the miniPDX model, and the olaparib combined with apatinib group had the strongest inhibitory effect on tumor cells.
- patient C advanced refractory prostate cancer, positive for TP53 mutation, took prostate biopsy tissue for miniPDX model construction, and the olaparib combined with apatinib group had the strongest inhibitory effect on tumor cells.
- patient D advanced refractory endometrial cancer, positive for TP53 mutation, took the tumor biopsy tissue to construct the miniPDX model, and the olaparib combined with apatinib group had the strongest inhibitory effect on tumor cells.
- patient E advanced refractory pancreatic cancer, positive for TP53 mutation, took the tumor biopsy tissue to construct the miniPDX model, and the olaparib combined with apatinib group had the strongest inhibitory effect on tumor cells.
- the above patients found that the anti-angiogenic drug (apatinib) combined with the PARP inhibitor (olaparib) had the strongest inhibitory effect on tumor cell proliferation, and these two drugs were used clinically.
- the combination achieved good efficacy, fully demonstrating the feasibility of the combination of these two drugs in the treatment of advanced refractory solid tumors with TP53 mutations.
Abstract
A drug for treating an advanced refractory solid tumor having a TP53 mutation, characterized in that the drug is a combination of an anti-angiogenic drug and a PARP inhibitor. The PARP inhibitor comprises one of or two or more of olaparib, niraparib, iniparib, talazoparib, rucaparib, and veliparib. The anti-angiogenic drug comprises one of or two or more of apatinib, pazopanib, cediranib, sorafenib, sunitinib, axitinib, bevacizumab, and anlotinib.
Description
本申请要求于2020年11月11日提交中国专利局、申请号为202011252897.9、发明名称为“一种治疗TP53突变的晚期难治性实体瘤的药物及应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。This application claims the priority of the Chinese patent application filed on November 11, 2020, with the application number of 202011252897.9 and the invention titled "A drug for the treatment of TP53-mutated advanced refractory solid tumors and its application". The entire contents of this application are incorporated by reference.
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。The invention belongs to the technical field of precision medicine, and in particular relates to a medicine and application for treating advanced refractory solid tumors with TP53 mutation.
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。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。Currently, the closest available technology: TP53 mutations are the most common tumor suppressor gene mutations in human tumors, with mutation frequencies ranging from 10% to 96%. Detrimental mutations in TP53 lead to cell cycle arrest and impaired DNA damage repair function, resulting in overexpression of target genes and genomic instability, thereby promoting tumorigenesis and progression. However, there is currently no effective approach to treat TP53-mutated tumors. Therefore, an effective therapeutic strategy that can target TP53-mutated tumors is urgently needed to improve the condition and prolong survival of these patients. Angiogenesis promotes the growth and spread of cancer cells and plays an important role in tumor formation and progression. Vascular endothelial growth factor (VEGF) activation of vascular endothelial growth factor receptor (VEGFR) is a key step in the angiogenesis signaling pathway. Blocking this pathway to treat tumors has achieved certain curative effects. For example, pazopanib in the treatment of renal cell carcinoma and apatinib in the treatment of gastric cancer have been approved for marketing. Currently commonly used anti-angiogenic drugs include pazopanib, sorafenib, sunitinib, apatinib, axitinib, and bevacizumab. Because of the lack of specific targets, antiangiogenic drugs can only temporarily prolong the survival of patients. Some studies have shown that patients with TP53 mutation can obtain better therapeutic response with anti-VEGF/VEGFR inhibitors, and TP53 mutation may be an effective therapeutic target.
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)、尼拉帕利(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。PARP inhibitors such as olaparib are already approved for the treatment of BRCA-mutated advanced ovarian and breast cancer. PARPs are a family of proteins that can bind to damaged DNA single strands and recruit DNA repair proteins to promote DNA single strand damage repair. Common PARP family proteins in humans are PARP1 and PARP2. The mechanism of action of PARP inhibitors is mainly based on the principle of synthetic lethality. By inhibiting the activity of PARP, the repair of DNA single-strand is difficult to complete, which leads to double-strand damage. DNA double-strand damage is mainly repaired by homologous recombination in the human body. In tumors with mutations in BRCA1, BRCA2, etc., this homologous recombination repair mechanism is defective, so when both repair pathways fail, cells die. Because normal cells in the human body do not divide as frequently as tumor cells, PARP inhibitors can exert a greater killing effect on tumor cells. Currently commonly used PARP inhibitors include olaparib, niraparib, iniparib, talazoparib, rucaparib, veliparib and the like. Antiangiogenic therapy combined with PARP inhibitors has shown certain anticancer efficacy in preclinical studies. Anti-angiogenic drugs can downregulate genes related to homologous recombination repair such as BRCA and RAD51, and at the same time can make cells in a hypoxic state, which can enhance the therapeutic effect of PARP inhibitors. Generated drugs can enhance the therapeutic effect of PARP inhibitors. Joyce F Liu and colleagues found that the anti-angiogenic drug cediranib combined with the PARP inhibitor olaparib was far more effective than olaparib monotherapy in recurrent ovarian cancer. All patients need to undergo genetic testing to detect TP53 mutations. At present, the genetic testing technology needs to be further standardized and the price of the test is relatively high; in addition, the price of targeted drugs is also relatively high. As targeted drugs are gradually included in medical insurance reimbursement, this problem Should be able to get some solution.
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、尼、阿西替尼、贝伐单抗等，缺少特异性的靶点。To sum up, the problems existing in the prior art are: the currently commonly used anti-angiogenic drugs include pazopanib, sorafenib, sunitinib, nigra, axitinib, bevacizumab, etc. specific target.
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。Difficulty in solving the above technical problems: Solving the problem of lack of specific targets for anti-angiogenic drugs requires more cell biology experiments and animal experiments, which may take a long time, and the exploration may not be smooth. Inventions may take a different approach.
发明内容SUMMARY OF THE INVENTION
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。Aiming at the problems existing in the prior art, the present invention provides a medicine and application for treating advanced refractory solid tumors with TP53 mutation.
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。The present invention is achieved in this way, a drug for the treatment of advanced refractory solid tumors with TP53 mutation, characterized in that the drug is a combination of an anti-angiogenesis drug and a PARP inhibitor.
所述抗血管生成药物的分子式为C
25H
27N
5O
4S：
The molecular formula of the anti-angiogenic drug is C 25 H 27 N 5 O 4 S:
所述PARP抑制剂的分子式为C
24H
23FN
4O
3：
The molecular formula of the PARP inhibitor is C 24 H 23 FN 4 O 3 :
进一步，所述PARP抑制剂包括奥拉帕利(olaparib)、尼拉帕利(niraparib)、iniparib、talazoparib、rucaparib、veliparib。Further, the PARP inhibitors include olaparib, niraparib, iniparib, talazoparib, rucaparib, and 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。Further, the drugs for treating advanced refractory solid tumors with TP53 mutation are apatinib and olaparib.
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。Another object of the present invention is to provide a method of using a drug for the treatment of advanced refractory solid tumors with TP53 mutation, apatinib 250 mg once a day, and olaparib 150 mg twice a day.
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。Another object of the present invention is to provide a medicament for the treatment of advanced refractory prostate cancer obtained by using the above medicament.
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。Another object of the present invention is to provide a medicament for the treatment of advanced refractory endometrial cancer obtained by using the above medicament.
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。Another object of the present invention is to provide a medicament for the treatment of advanced refractory pancreatic cancer obtained by using the above medicament.
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。Another object of the present invention is to provide a medicament for the treatment of advanced refractory lung cancer obtained by using the above medicament.
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。Another object of the present invention is to provide a medicament for the treatment of advanced refractory ovarian cancer obtained by using the above medicament.
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。Another object of the present invention is to provide a medicament for the treatment of advanced refractory renal cancer obtained by using the above medicament.
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。Another object of the present invention is to provide a medicament for the treatment of advanced refractory bladder cancer obtained by using the above medicament.
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。Another object of the present invention is to provide a medicament for the treatment of advanced refractory colorectal cancer obtained by using the above medicament.
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。Another object of the present invention is to provide a medicament for the treatment of advanced refractory gastric cancer obtained by using the above medicament.
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。Another object of the present invention is to provide a medicament for the treatment of advanced refractory breast cancer obtained by using the above medicament.
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。Another object of the present invention is to provide a medicament for the treatment of advanced refractory sarcoma obtained by using the above medicament.
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。Another object of the present invention is to provide a medicament for the treatment of advanced refractory metastases with unknown primary tumor obtained by using the above medicament.
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。In the present invention, the tumor of the TP53-mutated solid tumor patient can be significantly reduced by using an anti-angiogenesis drug in combination with a PARP inhibitor, which is a new idea. The results are undoubtedly meaningful for the treatment of tumor patients and prolong the life of tumor patients.
综上所述，本发明的优点及积极效果为：To sum up, the advantages and positive effects of the present invention are:
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。As mentioned in the background art, advanced solid tumors with TP53 mutation have a high degree of malignancy and cannot be effectively treated by the prior art, which further highlights the practicability and creativity of the new method of the present invention. We believe that some current drugs for the treatment of tumors have not been able to accurately target patients. It may be that apatinib combined with olaparib is not effective in patients with non-TP53-mutated tumors, precisely because the therapeutic target of TP53 mutation has been identified. Only by the point, the curative effect is reflected, which is also the charm of precision medicine.
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。The present invention utilizes anti-angiogenesis drugs combined with PARP inhibitors to treat advanced solid tumors with TP53 mutation, and achieves a miraculous curative effect. Antiangiogenic drugs combined with PARP inhibitors have shown certain anticancer efficacy in preclinical studies. Anti-angiogenic drugs can down-regulate genes related to homologous recombination repair such as BRCA and RAD51, and at the same time can make cells in a hypoxic state, which can enhance the therapeutic effect of PARP inhibitors.
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。In the present invention, the anti-angiogenic drug apatinib combined with the PARP inhibitor olaparib is used to treat the advanced solid tumor with TP53 mutation. At present, no such technical solution has been published in the form of papers or patents at home and abroad, and the efficacy of the technical solution has been obtained. clinically validated. Different mutational status of TP53 can predict the efficacy of anti-angiogenic drugs, PARP inhibitors or the combination of the two, and the efficacy of patients with TP53 missense mutations is significantly better than that of patients with TP53 loss-of-function mutations.
说明书附图Instruction drawings
图1是本发明实施例提供的奥拉帕利联合阿帕替尼组对患者A肿瘤细胞抑制作用效果示意图；1 is a schematic diagram of the inhibitory effect of olaparib combined with apatinib group on patient A tumor cells provided in the embodiment of the present invention;
图2是本发明实施例提供的奥拉帕利联合阿帕替尼组对患者B肿瘤细胞抑制作用效果示意图；2 is a schematic diagram of the inhibitory effect of olaparib combined with apatinib group on patient B tumor cells provided in the embodiment of the present invention;
图3是本发明实施例提供的奥拉帕利联合阿帕替尼组对患者C肿瘤细胞抑制作用效果示意图；3 is a schematic diagram of the inhibitory effect of olaparib combined with apatinib group on patient C tumor cells provided in the embodiment of the present invention;
图4是本发明实施例提供的奥拉帕利联合阿帕替尼组对患者D肿瘤细胞抑制作用效果示意图；4 is a schematic diagram of the inhibitory effect of olaparib combined with apatinib group on patient D tumor cells provided in the embodiment of the present invention;
图5是本发明实施例提供的奥拉帕利联合阿帕替尼组对患者E肿瘤细胞抑制作用效果示意图；Figure 5 is a schematic diagram of the inhibitory effect of olaparib combined with apatinib group on patient E tumor cells provided in the embodiment of the present invention;
图6是本发明实施例提供的干预和评价指标示意图。FIG. 6 is a schematic diagram of intervention and evaluation indicators provided by an embodiment of the present invention.
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。In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention, but not to limit the present invention.
下面结合附图对本发明的应用原理作详细的描述。The application principle of the present invention will be described in detail below with reference to the accompanying drawings.
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。The drugs for the treatment of advanced refractory solid tumors with TP53 mutation provided in the embodiments of the present invention are apatinib and olaparib.
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。When taking apatinib and olaparib, both are taken orally; due to the different tolerance of different patients, the lowest effective dose is generally taken, such as apatinib 250mg, once a day, olaparib 150mg, 2 times a day.
抗血管生成药物的分子式为C
25H
27N
5O
4S：
The molecular formula of the anti-angiogenic drug is C 25 H 27 N 5 O 4 S:
PARP抑制剂的分子式为C
24H
23FN
4O
3：
The molecular formula of the PARP inhibitor is C 24 H 23 FN 4 O 3 :
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。The application effect of the present invention will be described in detail below in conjunction with specific clinical examples.
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vs 3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！1. At present, 39 patients with TP53-mutated advanced refractory solid tumors (8 patients in the terminal stage of tumor, ECOG score 3-4) have been enrolled, involving 11 different cancers. Oral treatment with olaparib 150 mg bid combined with apatinib 250 mg qd was continued until disease progression or intolerable toxicity. The results showed that the overall objective response rate (ORR), disease control rate (DCR) and median progression-free time (PFS) were 33.3%, 82.0% and 5 months, respectively. Among them, patients with TP53 missense mutations had significantly better efficacy than patients with TP53 loss-of-function mutations, with ORR and PFS of 42.3% vs 15.4% and 6 months vs 3 months, respectively. The median overall survival (OS) has not been reached, and the combination therapy has mild adverse effects, the most common adverse reactions being fatigue, hypertension, and hand-foot-skin reactions. There were no treatment-related deaths. Overall, PARP inhibitors (olaparib, etc.) combined with anti-angiogenic drugs (such as apatinib) have shown significant efficacy and good safety in the treatment of patients with TP53-mutated advanced solid tumors, especially in Better results in subgroups with TP53 missense mutations!
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。Table 1 compares the efficacy of PARP inhibitor combined with antiangiogenic drugs and Weel inhibitor AZD1775 combined with carboplatin in patients with TP53-mutated advanced solid tumors. It can be seen that the solution of the present invention is significantly better than the prior art.
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Table 1 Comparison of the efficacy of PARP inhibitor combined with anti-angiogenic drugs and AZD1775 combined with carboplatin in the treatment of advanced solid tumors with TP53 mutation
| 奥拉帕利联合阿帕替尼Olaparib combined with apatinib | AZD1775联合卡铂AZD1775 combined with carboplatin | |
| 客观缓解率(ORR)Objective Response Rate (ORR) | 33.3％33.3% | 10％10% |
| 疾病控制率(DCR)Disease Control Rate (DCR) | 82.0％82.0% | 53％53% |
2、进行miniPDX模型验证结果病例说明；2. Carry out case description of miniPDX model verification results;
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。The miniPDX model is an animal experiment. It is a drug susceptibility test model established by transplanting primary human tumor cells into immunodeficient mice using a special method. Conduct drug sensitivity test research, screen out the optimal individualized drug regimen, and provide a scientific basis for patients' clinical drug selection.
具体实验步骤如下：The specific experimental steps are as follows:
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。① Collect patient tissue samples, digest them into single cell suspension in vitro, filter to remove tissue blocks and cell clumps, and remove cell debris.
②重悬肿瘤细胞，调整细胞浓度，灌装至Mini PDX评价系统装置。②Resuspend the tumor cells, adjust the cell concentration, and fill them into the Mini PDX evaluation system device.
③接种至实验小鼠(BALB/c-nude mice)，按预设好实验方案分组给药。③Inoculated into experimental mice (BALB/c-nude mice), and administered in groups according to the preset experimental plan.
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。④ The experiment was carried out for 7 days. After the experiment, the evaluation device was taken out, and the activity of tumor cells was detected by in vitro ATP method.
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。Figures 1 to 5 are partial experimental results showing that the combined regimen has excellent anti-tumor cell proliferation ability.
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。As shown in Figure 1, patient A, advanced refractory prostate cancer, positive for TP53 mutation, took liver metastases biopsy tissue for miniPDX model construction, and the olaparib combined with apatinib group had the strongest inhibitory effect on tumor cells.
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。As shown in Figure 2, patient B, advanced refractory prostate cancer, positive for TP53 mutation, took the biopsy tissue of lung metastases to construct the miniPDX model, and the olaparib combined with apatinib group had the strongest inhibitory effect on tumor cells.
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。As shown in Figure 3, patient C, advanced refractory prostate cancer, positive for TP53 mutation, took prostate biopsy tissue for miniPDX model construction, and the olaparib combined with apatinib group had the strongest inhibitory effect on tumor cells.
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。As shown in Figure 4, patient D, advanced refractory endometrial cancer, positive for TP53 mutation, took the tumor biopsy tissue to construct the miniPDX model, and the olaparib combined with apatinib group had the strongest inhibitory effect on tumor cells.
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。As shown in Figure 5, patient E, advanced refractory pancreatic cancer, positive for TP53 mutation, took the tumor biopsy tissue to construct the miniPDX model, and the olaparib combined with apatinib group had the strongest inhibitory effect on tumor cells.
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。Under the guidance of the miniPDX modeling drug susceptibility test, the above patients found that the anti-angiogenic drug (apatinib) combined with the PARP inhibitor (olaparib) had the strongest inhibitory effect on tumor cell proliferation, and these two drugs were used clinically. The combination achieved good efficacy, fully demonstrating the feasibility of the combination of these two drugs in the treatment of advanced refractory solid tumors with TP53 mutations.
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。The above descriptions are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements and improvements made within the spirit and principles of the present invention shall be included in the protection of the present invention. within the range.
Claims (18)
- 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；A drug for the treatment of advanced refractory solid tumors with TP53 mutation, characterized in that the drug is an anti-angiogenic drug combined with a PARP inhibitor combination;所述抗血管生成药物的分子式为C 25H 27N 5O 4S，结构式如式I所示： The molecular formula of the anti-angiogenic drug is C 25 H 27 N 5 O 4 S, and the structural formula is shown in formula I:
所述PARP抑制剂的分子式为C 24H 23FN 4O 3，结构式如式II所示： The molecular formula of the PARP inhibitor is C 24 H 23 FN 4 O 3 , and the structural formula is shown in formula II:
- 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；A drug for the treatment of advanced refractory solid tumors with TP53 mutation, characterized in that the drug is an anti-angiogenic drug combined with a PARP inhibitor combination;所述PARP抑制剂包括奥拉帕利、尼拉帕利、iniparib、talazoparib、rucaparib和veliparib中的一种或两种以上；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中的一种或两种以上。The PARP inhibitors include one or more of olaparib, niraparib, iniparib, talazoparib, rucaparib and veliparib; the anti-angiogenesis drugs include apatinib, pazopanib, One or more of dinib, sorafenib, sunitinib, axitinib, bevacizumab, and anlotinib.
- 如权利要求2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是奥拉帕利联合西地尼布，奥拉帕利联合安罗替尼或尼拉帕利联合安罗替尼。The drug for the treatment of TP53-mutated advanced refractory solid tumors according to claim 2, wherein the drug for the treatment of TP53-mutated advanced refractory solid tumors is olaparib combined with cediranib, olaparib Paliban in combination with anlotinib or niraparib in combination with anlotinib.
- 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。A method for using a drug for treating advanced refractory solid tumors with TP53 mutation, characterized in that apatinib is 250 mg once a day, and olaparib is 150 mg twice a day.
- 根据权利要求4所述的方法，其特征在于，所述TP53突变包括TP53错义突变。The method of claim 4, wherein the TP53 mutation comprises a TP53 missense mutation.
- 根据权利要求4所述的方法，其特征在于，所述晚期难治性实体瘤包括晚期难治性前列腺癌、晚期难治性子宫内膜癌、晚期难治性胰腺癌、晚期难治性肺癌、晚期难治性卵巢癌、晚期难治性肾癌、晚期难治性膀胱癌、晚期难治性结直肠癌、晚期难治性胃癌、晚期难治性乳腺癌、晚期难治性肉瘤或晚期难治性原发灶未明的转移瘤。The method of claim 4, wherein the advanced refractory solid tumor comprises advanced refractory prostate cancer, advanced refractory endometrial cancer, advanced refractory pancreatic cancer, and advanced refractory lung cancer , advanced refractory ovarian cancer, advanced refractory renal cancer, advanced refractory bladder cancer, advanced refractory colorectal cancer, advanced refractory gastric cancer, advanced refractory breast cancer, advanced refractory sarcoma or advanced Refractory metastases of unknown primary tumor.
- 一种利用权利要求1～3任意一项所述药物得到的治疗晚期难治性前列腺癌的药物。A medicine for treating advanced refractory prostate cancer obtained by using the medicine according to any one of claims 1 to 3.
- 一种利用权利要求1～3任意一项所述药物得到的治疗晚期难治性子宫内膜癌的药物。A medicine for treating advanced refractory endometrial cancer obtained by using the medicine according to any one of claims 1 to 3.
- 一种利用权利要求1～3任意一项所述药物得到的治疗晚期难治性胰腺癌的药物。A medicine for treating advanced refractory pancreatic cancer obtained by using the medicine according to any one of claims 1 to 3.
- 一种利用权利要求1～3任意一项所述药物得到的治疗晚期难治性肺癌的药物。A medicine for treating advanced refractory lung cancer obtained by using the medicine according to any one of claims 1 to 3.
- 一种利用权利要求1～3任意一项所述药物得到的治疗晚期难治性卵巢癌的药物。A medicine for treating advanced refractory ovarian cancer obtained by using the medicine according to any one of claims 1 to 3.
- 一种利用权利要求1～3任意一项所述药物得到的治疗晚期难治性肾癌的药物。A medicine for treating advanced refractory renal cancer obtained by using the medicine according to any one of claims 1 to 3.
- 一种利用权利要求1～3任意一项所述药物得到的治疗晚期难治性膀胱癌的药物。A medicine for treating advanced refractory bladder cancer obtained by using the medicine according to any one of claims 1 to 3.
- 一种利用权利要求1～3任意一项所述药物得到的治疗晚期难治性结直肠癌的药物。A medicine for treating advanced refractory colorectal cancer obtained by using the medicine according to any one of claims 1 to 3.
- 一种利用权利要求1～3任意一项所述药物得到的治疗晚期难治性胃癌的药物。A medicine for the treatment of advanced refractory gastric cancer obtained by using the medicine according to any one of claims 1 to 3.
- 一种利用权利要求1～3任意一项所述药物得到的治疗晚期难治性乳腺癌的药物。A medicine for treating advanced refractory breast cancer obtained by using the medicine according to any one of claims 1 to 3.
- 一种利用权利要求1～3任意一项所述药物得到的治疗晚期难治性肉瘤的药物。A medicine for treating advanced refractory sarcoma obtained by using the medicine according to any one of claims 1 to 3.
- 一种利用权利要求1～3任意一项所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。A medicament for treating advanced refractory metastases with unknown primary tumor obtained by using the medicament according to any one of claims 1 to 3.
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