Genetic and genomic determinants of homologous recombination repair deficiency as treatment selection markers for lethal prostate cancer

项目总结 同源重组(HR)缺陷(HRD)，尤其是由于双等位基因突变丢失 BRCA1/BRCA2/ATM(BRCA/ATM)在男性前列腺癌转移性去势抵抗患者中显著丰富 癌症(MCRPC)。这类患者有多种FDA批准的系统性延长生命疗法可供选择 包括阿比特龙、苯扎鲁胺和紫杉烷化疗，以及聚(ADP- 核糖)聚合酶(PARP)抑制剂治疗，目前仍在研究中。最近的几项研究 提示具有生殖系和/或体细胞HRD突变的患者可能反应更好(且持续时间更长 与HRD阴性患者相比，他们对新的激素治疗有更多的兴趣。这些研究表明 除了对PARP的抑制，有效的AR抑制也对mCRPC的HRD具有“合成致死性”。 然而，HRD的遗传/基因组决定因素及其在治疗选择中的作用仍不清楚。我们 提出一项以资源驱动、以患者为中心的研究，以确定HRD预测的遗传/基因组驱动因素 对阿比特龙和苯扎鲁胺的“深度”反应。我们假设mCRPC患者可以被归类为 根据HRD基因有害突变定义的HRD状态分为三组：1)种系/体细胞 HRD；2)仅体细胞HRD；3)阴性HRD；并且这些群在分子上是不同的，并且具有 AR靶向治疗和紫杉烷疗效预测指标的不同临床意义 化疗。为了解决总体假设，有必要建立临床和肿瘤/正常 样本队列，使mCRPC男性HRD的详细分子和临床特征成为可能。在……里面 具体目标1，我们将寻求确定HRD突变状态，包括体细胞和生殖系，在三个 现有的晚期/致命性前列腺癌队列使用基于血液的分析方法对HRD进行了浓缩。以特定的目标 2，我们将确定基于血液的分析所确定的HRD状态与治疗反应的关联 一线AR导向治疗(阿比特龙/苯扎鲁胺)和紫杉烷化疗治疗mCRPC 比较这三组男性的治疗结果。在具体目标3中，我们试图确定 通过血液检测和组织检测进一步确定的HRD状态的表达相关性 通过对患有致命性前列腺癌的男性手术标本进行RNA-Seq检测：1) 胚系/体细胞HRD；2)仅体细胞HRD；3)阴性HRD。拟议的工作解决了一个未满足的问题 在面临困难治疗的脆弱患者群体中需要关注液体活组织检查标记物 决定。此外，我们在确定HRD状态的临床和功能影响方面所做的努力 MCRPC患者队列将直接导致改善临床管理的治疗选择策略 以及临床试验的患者选择策略。

PROJECT SUMMARY Homologous recombination (HR) deficiency (HRD), particularly from biallelic mutational loss of BRCA1/BRCA2/ATM (BRCA/ATM), is significantly enriched in men with metastatic castration-resistant prostate cancer (mCRPC). Such patients have multiple FDA-approved systemic life-prolonging therapies to choose from, including abiraterone, enzalutamide, and taxane chemotherapies, as well as the possibility of poly(ADP- ribose) polymerase (PARP) inhibitor therapy which currently remains investigational. A few recent studies suggest that patients with germline and/or somatic HRD mutations may respond better (and for longer durations of time) to novel hormonal therapies than their HRD-negative counterparts. These studies suggest that in addition to PARP inhibition, potent AR suppression is also “synthetic lethal” with HRD in mCRPC. However, the genetic/genomic determinants of HRD and their role in treatment selection remain unknown. We propose a resource-driven, patient-centered study to determine the genetic/genomic drivers of HRD predicting “deep” response to abiraterone and enzalutamide. We hypothesize that mCRPC patients can be categorized into three groups according to HRD status defined by deleterious mutations in HRD genes: 1) germline/somatic HRD; 2) somatic-only HRD; 3) negative HRD; and that these groups are molecularly distinct, and have different clinical implications as predictive markers of response to AR-targeting therapies and taxane chemotherapies. To address the overall hypothesis, it is necessary to establish clinical and tumor/normal specimen cohorts that enable detailed molecular and clinical characterization of HRD in men with mCRPC. In Specific Aim 1, we will seek to ascertain the HRD mutations status, both somatic and germline, in three existing advanced/lethal prostate cancer cohorts enriched for HRD using blood-based assays. In Specific Aim 2, we will determine the association of HRD status defined by blood-based assays with treatment response to first-line AR-directed therapy (abiraterone/enzalutamide) and taxane chemotherapies in mCRPC patients by comparing treatment outcomes of men in these three groups. In Specific Aim 3, we seek to determine the expression correlates of HRD status defined by blood-based assays and further ascertained by tissue-based assays, by performing RNA-Seq in surgical specimens from men with lethal prostate cancer with: 1) germline/somatic HRD; 2) somatic-only HRD; and 3) negative HRD. The proposed work addresses an unmet need due to focus on liquid biopsy markers in a vulnerable patient population facing difficult treatment decisions. Also, our effort in defining the clinical and functional implications of HRD status in established cohorts of mCRPC patients will directly lead to treatment selection strategies to improve clinical management as well as patient selection strategies for clinical trials.