Mechanisms of PARP Inhibitor Resistance in Ovarian Cancer

卵巢癌 PARP 抑制剂耐药机制

基本信息

批准号：
9020939
负责人：
SCOTT H KAUFMANN
金额：
$ 40.39万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-23 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9020939
关键词：
Affect Antineoplastic Agents BRCA1 gene BRCA2 Mutation BRCA2 gene Biopsy Cancer Model Cancer Patient Cell Line Cells Cessation of life Cicatrix Cisplatin Clinical Complement DNA Damage DNA Double Strand Break DNA Repair DNA Repair Gene DNA Repair Pathway DNA Single Strand Break DNA-PKcs Defect Diagnosis Disabled Persons Disease-Free Survival Double Strand Break Repair Down-Regulation Epigenetic Process Epithelial ovarian cancer Fanconi&apos s Anemia Future G22P1 gene Gene Dosage Genes Genomic Instability Genomics Half-Life Health In Vitro Ku Protein LIG4 gene Maintenance Maintenance Therapy Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of pancreas Malignant neoplasm of prostate Messenger RNA MicroRNAs Mutation New Agents Newly Diagnosed Nuclear Export Oncogenes Pathway interactions Patients Phase II Clinical Trials Placebo Control Platinum Poly(ADP-ribose) Polymerases Pre-Clinical Model Protein Tyrosine Kinase Proteins Publishing Randomized Relapse Reporting Resistance Sampling Serous Single Strand Break Repair Somatic Mutation Time Translations Up-Regulation Work XRCC4 gene artemis base cancer cell cancer subtypes cancer type candidate identification chemotherapy cytotoxic design exome genome-wide homologous recombination in vivo inhibitor/antagonist insertion/deletion mutation insight interest mRNA Expression malignant breast neoplasm member mutant mutation carrier novel novel therapeutics objective response rate overexpression p53-binding protein 1 phase 2 study phase III trial pre-clinical predictive marker protein expression repaired research study resistance mechanism response small hairpin RNA targeted treatment tumor

项目摘要

DESCRIPTION (provided by applicant): The Fanconi anemia/homologous recombination (FA/HR) pathway is frequently silenced by mutations or epigenetic processes in several types of cancer, including high-grade serous ovarian cancer (HGSOC), basal breast cancer, and a subset of pancreatic and prostate cancers. As a result, high fidelity repair of DNA double- strand breaks is disabled, leading to genomic instability in these cancers. Inhibitors of the DNA repair protein poly(ADP-ribose) polymerase (PARP) have shown promising activity in HR-deficient preclinical models and response rates of 30-45% in BRCA1 or BRCA2 (BRCA1/2) mutation carriers with platinum-sensitive relapsed HGSOC. This project is designed to better understand why some BRCA1/2-mutant cancers respond to PARP inhibitors and others do not. Previous results from members of our investigative team have not only identified BRCA1/2 reversion mutations as a potential cause of platinum resistance in preclinical models and clinical samples, but also demonstrated that the cytotoxic effects of PARP inhibitors reflect activation of nonhomologous end-joining (NHEJ), an error-prone DNA double-strand break repair pathway, rather than inhibition of DNA single-strand break repair as originally thought. Importantly, inhibition or downregulation of any of a number of NHEJ proteins inhibits this error-prone repair and diminishes the cytotoxic effects of PARP inhibitors. This new understanding of PARP inhibitor action leads to the hypothesis that resistance of BRCA1/2-mutant cancers to PARP inhibitors can result from either reversion mutations or changes in DNA repair pathway proteins that abrogate the action of the PARP inhibitors. Consistent with this hypothesis, our further studies in a BRCA2-mutant preclinical ovarian cancer model have demonstrated that selection for PARP inhibitor resistance results in either downregulation of NHEJ proteins or overexpression of Rad51, an HR protein downstream of BRCA2. To build on these findings we now propose to: i) further assess the impact of NHEJ protein downregulation on PARP inhibitor sensitivity in vitro and in vivo, ii) examine how Rad51 is upregulated to induce PARP inhibitor resistance; iii) perform a whole-exome shRNA screen looking for additional mechanisms of PARP inhibitor resistance in BRCA1/2-mutant ovarian cancer lines in vitro; and iv) examine two unique sets of cancer biopsies from patients receiving single-agent PARP inhibitor therapy to evaluate the potential importance of these resistance mechanisms in the clinical setting. Collectively, these studies will provide new insight into mechanisms of PARP inhibitor resistance that will enable future selection of ovarian cancer patients most likely to benefit from these promising new drugs.

描述（由申请人提供）：范可尼贫血/同源重组 (FA/HR) 通路经常因多种癌症类型的突变或表观遗传过程而沉默，包括高级别浆液性卵巢癌 (HGSOC)、基底乳腺癌和胰腺癌和前列腺癌的子集。结果，DNA双链断裂的高保真修复被禁用，导致这些癌症的基因组不稳定。 DNA 修复蛋白聚（ADP-核糖）聚合酶 (PARP) 抑制剂在 HR 缺陷的临床前模型中显示出良好的活性，并且在铂敏感复发性 BRCA1 或 BRCA2 (BRCA1/2) 突变携带者中的缓解率为 30-45% HGSOC。该项目旨在更好地了解为什么一些 BRCA1/2 突变癌症对 PARP 抑制剂有反应，而另一些则没有。我们研究团队成员之前的结果不仅在临床前模型和临床样本中确定了 BRCA1/2 回复突变是铂类耐药的潜在原因，而且还证明 PARP 抑制剂的细胞毒性作用反映了非同源末端连接 (NHEJ) 的激活），一种容易出错的DNA双链断裂修复途径，而不是像最初认为的那样抑制DNA单链断裂修复。重要的是，抑制或下调任何 NHEJ 蛋白都会抑制这种容易出错的修复，并减弱 PARP 抑制剂的细胞毒性作用。对 PARP 抑制剂作用的这种新认识导致了这样的假设：BRCA1/2 突变型癌症对 PARP 抑制剂的耐药性可能是由于回复突变或 DNA 修复途径蛋白的变化导致 PARP 抑制剂的作用失效。与这一假设一致，我们在 BRCA2 突变临床前卵巢癌模型中的进一步研究表明，选择 PARP 抑制剂耐药性会导致 NHEJ 蛋白下调或 Rad51（BRCA2 下游的 HR 蛋白）过度表达。基于这些发现，我们现在建议：i) 进一步评估 NHEJ 蛋白下调对体外和体内 PARP 抑制剂敏感性的影响，ii) 检查 Rad51 如何上调以诱导 PARP 抑制剂耐药性； iii) 进行全外显子组 shRNA 筛选，寻找体外 BRCA1/2 突变卵巢癌系中 PARP 抑制剂耐药性的其他机制； iv) 检查接受单药 PARP 抑制剂治疗的患者的两组独特的癌症活检，以评估这些耐药机制在临床环境中的潜在重要性。总的来说，这些研究将为 PARP 抑制剂耐药机制提供新的见解，使未来能够选择最有可能从这些有前途的新药中受益的卵巢癌患者。