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

项目摘要 同源重组（HR）缺陷（HRD），特别是来自双等位基因突变缺失， BRCA 1/BRCA 2/ATM（BRCA/ATM）在转移性去势抵抗性前列腺患者中显著富集 癌症（mCRPC）。这类患者有多种FDA批准的延长生命的全身疗法可供选择 包括阿比特龙、恩杂鲁胺和紫杉烷化疗，以及聚（ADP- 核糖）聚合酶（PARP）抑制剂疗法，其目前仍在研究中。最近的一些研究 提示具有生殖系和/或体细胞HRD突变的患者可能反应更好（并且持续更长时间 持续时间）比他们的HRD阴性对应的新的激素治疗。这些研究表明 除了PARP抑制外，强效AR抑制也是mCRPC中HRD的“合成致死”。 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然未知。我们 提出一项资源驱动、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 对阿比特龙和恩杂鲁胺的“深度”反应。我们假设mCRPC患者可以分为 根据由HRD基因中的有害突变定义的HRD状态分为三组：1）种系/体细胞 HRD; 2）仅体细胞HRD; 3）阴性HRD;并且这些组在分子上是不同的，并且具有 作为AR靶向治疗和紫杉烷反应的预测标志物的不同临床意义 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，能够详细描述mCRPC男性中HRD的分子和临床特征。在 具体目标1，我们将寻求确定HRD突变状态，体细胞和生殖系，在三个， 使用基于血液的测定富集HRD的现有晚期/致死性前列腺癌群组。具体目标 2，我们将确定HRD状态与治疗反应的关系， 一线AR导向治疗（阿比特龙/enzalutamide）和紫杉烷类化疗在mCRPC患者中的应用， 比较这三组男性的治疗结果。在具体目标3中，我们寻求确定 HRD状态的表达相关性通过基于血液的测定来定义，并通过基于组织的 通过在来自患有致死性前列腺癌的男性的手术标本中进行RNA-Seq，使用：1） 胚系/体细胞HRD; 2）仅体细胞HRD;和3）阴性HRD。拟议的工作涉及一个未得到满足的 由于在面临困难治疗的弱势患者人群中关注液体活检标记物， 决策此外，我们在确定HRD状态的临床和功能影响方面的努力， mCRPC患者队列将直接导致治疗选择策略，以改善临床管理 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.