Poisoning of PARP and Topoisomerase I to Treat Ovarian Cancer

PARP 和拓扑异构酶 I 中毒治疗卵巢癌

• 批准号: 7727445
• 负责人: SCOTT H KAUFMANN
• 金额: $ 31.58万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7727445
• 关键词: Accounting; Affect; Apoptotic; Ataxia-Telangiectasia-Mutated protein kinase; BRCA2 gene; Base Excision Repairs; Binding; Biometry; Biostatistics Core; Cancer Patient; Cancer cell line; Case Fatality Rates; Cells; Cessation of life; Checkpoint kinase 1; Clinic; Clinical; Complex; DNA; DNA Damage; DNA Repair Pathway; DNA lesion; Development; Diagnosis; Disabled Persons; Disease; Disease Resistance; Disease remission; Enrollment; Enzymes; Epithelial ovarian cancer; Event; FDA approved; Future; Genomics; Instruction; Investigational Drugs; Ions; Laboratories; Lead; Letters; Life; Liposomal Doxorubicin; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Mind; Neoplasms; Nuclear; Operative Surgical Procedures; Ovarian; PARP inhibition; Partial Remission; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phosphotransferases; Platinum; Poisoning; Poly(ADP-ribose) Polymerases; Proteins; Recurrence; Refractory; Relapse; Reporting; Reproduction spores; Research Design; Sampling; Scaffolding Protein; Series; Signal Transduction; Signal Transduction Pathway; Staging; Testing; Therapeutic; Topotecan; Treatment Protocols; Tumor Debulking; Type I DNA Topoisomerases; United States; Woman; XRCC1 gene; base; cancer cell; chemotherapy; cytotoxic; cytotoxicity; design; effective therapy; gemcitabine; human TOP1 protein; improved; inhibitor/antagonist; insight; killings; mortality; mutant; patient registry; prevent; programs; repaired; response; response marker; Accounting; Affect; Apoptotic; Ataxia-Telangiectasia-Mutated protein kinase; BRCA2 gene; Base Excision Repairs; Binding; Biometry; Biostatistics Core; Cancer Patient; Cancer cell line; Case Fatality Rates; Cells; Cessation of life; Checkpoint kinase 1; Clinic; Clinical; Complex; DNA; DNA Damage; DNA Repair Pathway; DNA lesion; Development; Diagnosis; Disabled Persons; Disease; Disease Resistance; Disease remission; Enrollment; Enzymes; Epithelial ovarian cancer; Event; FDA approved; Future; Genomics; Instruction; Investigational Drugs; Ions; Laboratories; Lead; Letters; Life; Liposomal Doxorubicin; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Mind; Neoplasms; Nuclear; Operative Surgical Procedures; Ovarian; PARP inhibition; Partial Remission; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phosphotransferases; Platinum; Poisoning; Poly(ADP-ribose) Polymerases; Proteins; Recurrence; Refractory; Relapse; Reporting; Reproduction spores; Research Design; Sampling; Scaffolding Protein; Series; Signal Transduction; Signal Transduction Pathway; Staging; Testing; Therapeutic; Topotecan; Treatment Protocols; Tumor Debulking; Type I DNA Topoisomerases; United States; Woman; XRCC1 gene; base; cancer cell; chemotherapy; cytotoxic; cytotoxicity; design; effective therapy; gemcitabine; human TOP1 protein; improved; inhibitor/antagonist; insight; killings; mortality; mutant; patient registry; prevent; programs; repaired; response; response marker

Ovarian cancer has the highest case fatality rate of any gynecological malignancy, killing 70% of patients and accounting for almost 16,000 deaths in the U.S. annually. While most women initially respond to platin-based chemotherapy, the high relapse rate and poor response to subsequent therapy highlight the need for more effective therapy for platin-resistant disease. Our previous studies examining the action of topotecan (TPT), a topoisomerase I (topo l)-directed agent that is approved for the second-line treatment of ovarian cancer, have demonstrated that TPT induces replication fork stalling followed by activation of a kinase cascade involving ATR and checkpoint kinase 1. Building on reports that poly(ADP-ribose) polymerase-1 (PARP1) is involved in restarting stalled replication forks as well as reversing trapped topo I- DNA complexes, we have more recently demonstrated that the PARP inhibitor ABT-888 enhances TPT cytotoxicity in ovarian cancer cell lines. Even though this sensitization is more prominent in BRCA1/2- deficient cells, it also occurs in ovarian cancer cells with wildtype BRCAI and BRCA2. Moreover, this sensitization occurs at ABT-888 concentrations that are 20-fold lower than those required to kill BRCAI/2- deficient cells directly. Additional results indicate that ABT-888 is sensitizing cells through a base excision repair pathway that involves XRCC1 and suggest that PARP1 must be present for this sensitization. To further study this interaction between TPT and ABT-888, as well as extend the potential benefits of PARP inhibitor therapy to as large a subset of ovarian cancer patients as possible, we now propose to: Aim 1: Identify the mechanism by which PARP1 inhibition enhances the antiproliferative effects of TPT In ovarian cancer cells by further elucidating the DNA repair pathway that is critical for ABT- 888 mediated sensitization and determining how inhibited PARP1 actively sensitizes cells to TPT. Aim 2: Determine the mechanism of ABT-888 Induced antiproliferative effects in BRCA1/2-deflcient cells by identifying the endogenous DNA lesions that contribute to the cytotoxicity of ABT-888 as well as examining how PARP inhibition contributes to this demise. Aim 3: Evaluate the ability of a series of markers to predict response to the TPT/ABT-888 combinat¿ ion in a CTEP-sponsored phase II trial In patients with relapsed ovarian cancer. Samples from patients enrolled on this trial will provide a unique opportunity to search for potential predictive markers of response to this regimen. These studies, which make extensive use of the Biospecimens/Patient Registry and Biostatistics Cores of the Mayo Ovarian SPORE, are designed to increase understanding of the action of the PARP inhibitor ABT- 888, both alone and in combination with TPT, in ovarian cancer, thereby advancing clinical development of the PARP inhibitor as a potentially promising ovarian cancer therapeutic. RELEVANCE (See instructions): Ovarian cancer is a lethal malignancy that claims 16,000 lives annually in the United States. ABT-888 is an investigational drug that enhances the ability of topotecan, an FDA-approved treatment for ovarian cancer, to kill ovarian cancer cells in the laboratory. The present studies are designed to not only increase understanding of the mechanism by which ABT-888 exerts its effects, but also identify ovarian cancer patients who are most likely to respond to the topotecan/ABT-888 combination in the clinic.

卵巢癌在任何妇科恶性肿瘤中的病例死亡率最高，造成70％ 每年在美国，患者和近16,000人死亡。大多数妇女最初回应 对于基于柏拉图的化学疗法，高继电器率和对随后治疗的反应不良突出 需要对抗柏拉丁疾病进行更有效的治疗。我们以前研究了 TOPOTECAN（TPT），拓扑异构酶I（TOPO L）指导的代理，已批准用于二线治疗的 卵巢癌已证明TPT诱导复制叉停滞，然后激活A 涉及ATR和检查点激酶1的激酶级联反应。 聚合酶-1（PARP1）参与重新启动停滞的复制叉以及逆转捕获的topo i- DNA复合物，我们最近证明了PARP抑制剂ABT-888增强了TPT 卵巢癌细胞系中的细胞毒性。即使这种敏感性在BRCA1/2-中更为突出 细胞不足，它也发生在野生型BRCAI和BRCA2的卵巢癌细胞中。而且，这 敏化发生在ABT-888浓度下，比杀死Brcai/2-的浓度低20倍。 直接缺陷细胞。其他结果表明，ABT-888正在通过基本惊喜使细胞敏感 涉及XRCC1的修复途径，并建议为此灵敏度存在PARP1。 进一步研究TPT和ABT-888之间的这种相互作用，并扩大了潜在的好处 PARP抑制剂治疗以尽可能大的卵巢癌患者部分，我们现在建议： AIM 1：确定PARP1抑制增强抗增殖作用的机制 通过进一步阐明对ABT-至关重要的DNA修复途径，在卵巢癌细胞中的TPT 888介导的灵敏度，并确定抑制PARP1如何主动感应细胞对TPT。 AIM 2：确定BRCA1/2-偏氟的ABT-888诱导抗增殖作用的机制 通过鉴定有助于ABT-888的细胞毒性的内源性DNA病变作为 以及研究PARP抑制如何导致这种灭亡。 目标3：评估一系列标记预测对TPT/ABT-888组合的响应的能力 在CTEP赞助的II期试验中，离子在继电器卵巢癌患者中。来自 参加此试验的患者将为寻找潜在的预测性提供独特的机会 对该方案的反应标记。 这些研究广泛使用了生物测量/患者注册表和生物统计核心 蛋黄酱卵巢孢子旨在提高对PARP抑制剂ABT-的作用的理解 888，单独和与TPT结合，在卵巢癌中，从而进步 PARP抑制剂是一种潜在有前途的卵巢癌疗法。 相关性（请参阅说明）：卵巢癌是一种致命的恶性肿瘤 国家。 ABT-888是一种研究药物，可增强拓扑托克（FDA）批准的能力 治疗卵巢癌，以杀死实验室的卵巢癌细胞。目前的研究是设计的 不仅要增加对ABT-888执行其效果的机制的理解，还可以确定 最有可能对诊所中拓扑替康/ABT-888组合做出反应的卵巢癌患者。