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

项目总结/摘要： 目前，转移性去势抵抗性前列腺癌（mCRPC）几乎总是致命的。有 迫切需要针对个体肿瘤中存在的弱点定制mCRPC治疗。串扰 DNA损伤反应和雄激素受体（AR）信号之间的联系代表了 个性化前列腺癌治疗的前景。在本申请中，我们将调查 三种最常见的DNA改变的机制和治疗意义 mCRPC中的修复基因：BRCA 2、BRCA 1和ATM。使用新的体外和体内模型， 同源重组（HR）缺陷，我们将询问BRCA 2与BRCA 1与 ATM改变，两个拷贝与一个拷贝畸变，以及截短与非截短突变， 同源重组、雄激素受体（AR）信号传导和对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结果 与这些代理人。最后，我们将使用基于CRISPR的功能基因组方法来鉴定新的 mCPRC模型中的遗传脆弱性可以为下一代治疗策略提供信息 并指导临床试验的开展。我们的研究将通过以下方式显著推进mCRPC领域：1） 开发第一个HR缺陷的人类临床前模型，2）功能性表征最 mCRPC中普遍存在的BRCA 2、BRCA 1和ATM改变，3）更好地定义 定义mCRPC对PARPi和AR导向疗法的反应的途径，以及4）发现 影响这些反应的新靶点。考虑到BRCA 2、BRCA 1和ATM的流行程度， 在其他癌症，包括乳腺癌、卵巢癌和胰腺癌中， 这些研究揭示的机制将具有远远超出mCRPC领域的临床意义， 并将代表基于肿瘤遗传学的个体化癌症治疗的进步 改变。

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.