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）：在几种类型的癌症中的突变或表观遗传过程，包括高级卵巢癌（HGSOC），基底乳腺癌，胰腺癌和胰腺癌和前列腺癌的子集，通常会沉默的Fanconi贫血/同源重组（FA/HR）途径。结果，DNA双链断裂的高忠诚度修复是禁用的，导致这些癌症的基因组不稳定性。 DNA修复蛋白聚（ADP-核糖）聚合酶（PARP）的抑制剂在BRCA1或BRCA1（BRCA1/2）突变携带者中具有30-45％的HR缺乏临床前模型中的活性和铂敏感性复发性HGSOC的反应率为30-45％。该项目旨在更好地理解为什么某些BRCA1/2突变癌对PARP抑制剂做出反应，而其他癌症则没有反应。我们调查团队成员的先前结果不仅确定了临床前模型和临床样本中铂耐药性的潜在原因，而且还证明了PARP抑制剂的细胞毒性效应反映了非系统性终端限制的激活（NHEJ），而不是修复dna sings path，而不是修复pterna，而不是修复pterna，而不是对plove tra的修复。重要的是，抑制或下调许多NHEJ蛋白中的任何一种抑制了这种容易出错的修复，并减少了PARP抑制剂的细胞毒性作用。对PARP抑制剂作用的这种新理解导致了这样的假设：BRCA1/2突变癌对PARP抑制剂的耐药性可能是由恢复突变或DNA修复途径蛋白的变化导致的，从而消除了PARP抑制剂的作用。与这一假设一致，我们在BRCA2突变型临床前卵巢癌模型中的进一步研究表明，对PARP抑制剂耐药性的选择会导致NHEJ蛋白的下调或Rad51的过表达，这是BRCA2下游的HR蛋白。为了基于这些发现，我们现在建议：i）进一步评估NHEJ蛋白下调对PARP抑制剂敏感性在体外和体内的影响，ii）ii）检查如何上调RAD51以诱导PARP抑制剂的耐药性； iii）在BRCA1/2-突变卵巢癌系中，进行全外生shRNA筛查，以寻找PARP抑制剂耐药性的其他机制； iv）检查接受单药PARP抑制剂疗法的患者的两组独特的癌症活检，以评估这些抗药性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抑制剂耐药性机制提供新的见解，这将使未来的卵巢癌患者最有可能从这些有希望的新药中受益。