Targeting Somatic Homologous Recombination in Solid Tumors

靶向实体瘤中的体细胞同源重组

• 批准号: 8403813
• 负责人: MIGUEL A VILLALONA-CALERO
• 金额: $ 47.9万
• 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/8403813
• 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; 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; screening; 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.

描述（由申请人提供）：BRCA基因纯合缺乏症已被确定为对聚ADP-核糖聚合酶（PARP）抑制剂反应的预测因子。ABT-888就是这样一种化合物。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，在已经缺乏另一种修复机制的患者中，抑制一种修复机制会导致肿瘤死亡。尽管生殖系BRCA缺乏的癌症患者数量很少，但BRCA只是在同一修复途径中合作的近20个基因中的一个。这一途径被命名为范可尼贫血（FA）途径，因为存在一种以发育异常、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中的一个缺陷驱动。我们假设，大量不同器官和组织学的患者在这一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。这种益处在诱导DNA损伤后更为显著。一种能够从整体上检查这一途径的功能并实际应用于大规模筛查的测试对于识别这些患者是必要的。我们相信我们已经开发了这样一种测试，并且已经在不同组织学的患者肿瘤中产生了这种途径的体细胞缺陷的初步数据。在这个提议中，我们将：1-筛选不同组织学部位的癌症患者，以识别肿瘤中FA通路的功能缺陷；2-建立用PARP抑制剂ABT- 888作为长期单药治疗FA缺陷肿瘤患者的安全性和实用性；3-建立丝裂霉素C联合ABT-888治疗FA缺陷肿瘤患者的安全性和实用性；以及4-生成能够评估和优化DNA断裂剂和PARP抑制剂组合的体外和体内系统。