Targeting Somatic Homologous Recombination in Solid Tumors

靶向实体瘤中的体细胞同源重组

• 批准号: 8204586
• 负责人: MIGUEL A VILLALONA-CALERO
• 金额: $ 51.66万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204586
• 关键词: Accounting; Base Excision Repairs; Cancer Patient; Cessation of life; Clinic; Clinical; Clinical Trials; Complex; DNA; DNA Damage; Data; Defect; Development; Disease; Double Strand Break Repair; Enzymes; Failure; Fanconi' s Anemia; Genes; Germ Lines; Heterogeneity; Histology; Human; In Vitro; Inherited; Integration Host Factors; Knowledge; Learning; Malignant Neoplasms; Mismatch Repair; Mitomycins; Molecular Target; Mutation; Names; Nucleotide Excision Repair; Organ; Pancytopenia; Pathway interactions; Patients; Poly(ADP-ribose) Polymerases; Predisposition; Process; Radiation; Resources; Safety; Screening for cancer; Screening procedure; Signal Transduction; Site; Solid Neoplasm; Stratification; Syndrome; System; Technology; Testing; Therapeutic; Tumor Tissue; Work; chemotherapy; design; experience; homologous recombination; in vivo; inhibitor/antagonist; interest; novel; public health relevance; repair enzyme; repaired; response; treatment strategy; tumor

DESCRIPTION (provided by applicant): BRCA gene homozygous deficiency has been identified as a predictor of response to poly ADP- ribose polymerase (PARP) inhibitors. ABT-888 is one of such compounds. A closer look at BRCA function shows that BRCA is involved in homologous recombination (HR), an example of double strand break repair. This would suggest that inhibiting a repair mechanism in patients already deficient for another leads to tumor death. Although the numbers of cancer patients with germ line BRCA deficiency are low, BRCA is just one of close to 20 genes that collaborate in the same repair pathway. This pathway has been named the Fanconi Anemia (FA) pathway, given the presence of a hereditary syndrome characterized by developmental abnormalities, progressive bone marrow failure and cancer predisposition, driven by a defect in one of several genes of this pathway. We have hypothesized that a substantial number of patients across different organs and histologies have somatic deficiency in at least one gene in this pathway and that these patients are more likely to derive benefit from PARP inhibition. This benefit would be more significant following induced DNA damage. A test that could examine the functionality of this pathway as a whole and that could be practically applied for large-scale screening would be necessary to identify these patients. We believe we have developed such a test, and have generated preliminary data for somatic deficiency of this pathway in patients' tumors across several histologies. In this proposal we will: 1- screen cancer patients across different histological sites to identify those with functional defects in the FA pathway in their tumors; 2- establish the safety and practicality of treating patients with FA deficient tumors with the PARP inhibitor ABT- 888 as protracted monotherapy; 3- establish the safety and practicality of treating patients with FA deficient tumors with the combination of mitomycin C and ABT-888; and 4- generate and in vitro and in vivo system capable of evaluating and optimizing combinations of DNA breaking agents and PARP inhibitors. PUBLIC HEALTH RELEVANCE: Experience with novel agents that have been designed to interfere with the repair process suggests that patients who have additional defects in repair enzymes are more likely to benefit from these treatments. We have developed a test that can effectively screen patients for the functionality of the Fanconi anemia repair pathway, which is represented by more than 20 genes, all of which need to work together for repair to occur. In this proposal, we will select patients with functional defects in this pathway for treatment with the repair inhibitor ABT-888 as monotherapy and in combination with chemotherapy. We hypothesize that these patients will derive substantial clinical benefit from such treatment.

描述（由申请方提供）：BRCA基因纯合缺陷已被确定为对聚ADP-核糖聚合酶（PARP）抑制剂反应的预测因子。ABT-888就是其中之一。对BRCA功能的进一步研究表明，BRCA参与同源重组（HR），这是双链断裂修复的一个例子。这表明，抑制已经缺乏另一种修复机制的患者的修复机制会导致肿瘤死亡。虽然生殖细胞BRCA缺陷的癌症患者数量很低，但BRCA只是在同一修复途径中合作的近20个基因之一。该途径已被命名为范可尼贫血（FA）途径，因为存在以发育异常、进行性骨髓衰竭和癌症易感性为特征的遗传综合征，由该途径的几个基因之一的缺陷驱动。我们假设，不同器官和组织学的大量患者在该途径中至少有一个基因存在体细胞缺陷，这些患者更有可能从PARP抑制中获益。在诱导DNA损伤后，这种益处将更加显著。有必要进行一项测试，以检查整个通路的功能，并实际应用于大规模筛查，以确定这些患者。我们相信我们已经开发了这样一种测试，并且已经生成了几种组织学类型的患者肿瘤中该途径体细胞缺陷的初步数据。在本提案中，我们将：1-筛选不同组织学部位的癌症患者以鉴定在其肿瘤中FA途径中具有功能缺陷的那些; 2-确定用PARP抑制剂ABT- 888作为长期单一疗法治疗患有FA缺陷型肿瘤的患者的安全性和实用性; 3-确定用丝裂霉素C和ABT-888的组合治疗患有FA缺陷型肿瘤的患者的安全性和实用性;和4-产生能够评价和优化DNA断裂剂和PARP抑制剂的组合的体外和体内系统。 公共卫生关系：设计用于干扰修复过程的新型药物的经验表明，修复酶有额外缺陷的患者更有可能从这些治疗中受益。我们开发了一种测试，可以有效地筛选患者的范可尼贫血修复途径的功能，该途径由20多个基因代表，所有这些基因都需要共同努力才能进行修复。在这项提案中，我们将选择在这一途径中有功能缺陷的患者，用修复抑制剂ABT-888作为单药治疗和与化疗联合治疗。我们假设这些患者将从这种治疗中获得实质性的临床益处。