DNA repair alterations in metastatic prostate cancer: functional and therapeutic implications

项目摘要/摘要： 转移性去势耐药前列腺癌(MCRPC)目前几乎总是致命的。的确有 迫切需要针对个别肿瘤中存在的脆弱性量身定做mCRPC疗法。串扰 在DNA损伤反应和雄激素受体(AR)信号之间代表了最重要的 前列腺癌个人化治疗大有可为。在此应用程序中，我们将调查 三种最常见DNA改变的机制和治疗意义 MCRPC中的修复基因：BRCA2、BRCA1和ATM。利用新的体外和体内模型 同源重组(HR)不足，我们将询问BRCA2、BRCA1和 ATM改变，两个拷贝与一个拷贝像差，截断突变与非截断突变 同源重组，雄激素受体(AR)信号转导，以及对PARP抑制剂或AR- 定向治疗。然后，我们将在接受治疗的mCRPC患者的独特队列中验证这些发现。 和这些特工在一起。最后，我们将使用基于CRISPR的功能基因组方法来鉴定新的 可为下一代治疗策略提供信息的mCPRC模型中的遗传脆弱性 指导临床试验发展。我们的研究将在以下方面显著推进mCRPC领域：1) 建立第一个人类HR缺乏的临床前模型，2)功能特征 MCRPC中流行的BRCA2、BRCA1和ATM更改，3)更好地定义了机制 定义mCRPC对PARPI和AR导向疗法的反应的途径，以及4)发现 影响这些反应的新目标。鉴于BRCA2、BRCA1和ATM的流行 其他癌症的改变，包括乳腺癌、卵巢癌和胰腺癌， 这些研究发现的机制将具有远远超出mCRPC领域的临床意义， 这将代表着基于肿瘤基因的个体化癌症治疗的进步 改装。

PROJECT SUMMARY / ABSTRACT: Metastatic castration-resistant prostate cancer (mCRPC) is, at present, almost invariably fatal. There is an urgent need to tailor mCRPC therapy to vulnerabilities present within individual tumors. Crosstalk between DNA damage response and androgen receptor (AR) signaling represents one of the most promising opportunities for personalizing prostate cancer therapy. In this application, we will investigate the mechanistic and therapeutic implications of alterations in the three most commonly altered DNA repair genes in mCRPC: BRCA2, BRCA1, and ATM. Using novel in vitro and in vivo models of homologous recombination (HR) deficiency, we will interrogate the impact of BRCA2 vs. BRCA1 vs. ATM alterations, two copy vs. one copy aberrations, and truncating vs. non-truncating mutations on homologous recombination, androgen receptor (AR) signaling, and response to PARP inhibitors or AR- directed therapies. We will then validate these findings in unique cohorts of mCRPC patients treated with these agents. Finally, we will use CRISPR-based functional genomic approaches to identify novel genetic vulnerabilities in mCPRC models that can inform the next generation of therapeutic strategies and guide the development of clinical trials. Our study will significantly advance the mCRPC field by: 1) developing the first human preclinical models of HR deficiency, 2) functionally characterizing the most prevalent BRCA2, BRCA1, and ATM alterations in mCRPC, 3) better defining the mechanistic pathways that define the response of mCRPC to PARPi and AR-directed therapies, and 4) discovering novel targets that influence these responses. Given the prevalence of BRCA2, BRCA1, and ATM alterations in other cancers, including breast, ovarian, and pancreatic adenocarcinomas, the mechanisms uncovered by these studies will have clinical implications far beyond the mCRPC space, and will represent an advance towards individualizing cancer therapy based on tumor genetic alterations.