Targeting Somatic Homologous Recombination in Solid Tumors

靶向实体瘤中的体细胞同源重组

基本信息

批准号：
8101174
负责人：
MIGUEL A VILLALONA-CALERO
金额：
$ 52.22万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/8101174
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&apos 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

项目摘要

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（由申请人提供）：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 就是此类化合物之一。仔细观察 BRCA 功能表明，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。尽管患有生殖系 BRCA 缺陷的癌症患者数量很少，但 BRCA 只是在同一修复途径中协作的近 20 个基因之一。该途径被命名为范可尼贫血 (FA) 途径，因为存在一种遗传综合征，其特征是发育异常、进行性骨髓衰竭和癌症易感性，这是由该途径的几个基因之一的缺陷驱动的。我们假设，大量不同器官和组织学的患者在该途径中至少有一个基因存在体细胞缺陷，并且这些患者更有可能从 PARP 抑制中获益。在诱导 DNA 损伤后，这种益处会更加显着。需要进行一项测试来检查该通路的整体功能，并且可以实际应用于大规模筛查，以识别这些患者。我们相信我们已经开发了这样的测试，并且已经生成了跨多种组织学的患者肿瘤中该途径的体细胞缺陷的初步数据。在该提案中，我们将： 1- 筛查不同组织学部位的癌症患者，以识别肿瘤中 FA 通路存在功能缺陷的患者； 2- 确定用 PARP 抑制剂 ABT-888 作为长期单一疗法治疗 FA 缺乏肿瘤患者的安全性和实用性； 3-确定丝裂霉素C和ABT-888联合治疗FA缺乏肿瘤患者的安全性和实用性； 4-生成能够评估和优化DNA断裂剂和PARP抑制剂的组合的体外和体内系统。公共健康相关性：旨在干扰修复过程的新型药物的经验表明，修复酶存在其他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，可以有效筛查患者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发生修复。在本提案中，我们将选择该通路存在功能缺陷的患者接受修复抑制剂 ABT-888 作为单一疗法和联合化疗的治疗。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。