Project 1: Genomic Predictors of Clinical Outcomes and Response to Targeted Therapy in Advanced Prostate Cancer

摘要/摘要 临床测序直到最近才开始为FDA批准的个体化疗法的选择提供信息 前列腺癌患者。FDA最近批准鲁卡帕利布和奥拉帕利布治疗男性转移性癌症 耐去势前列腺癌具有DNA损伤修复(DDR)基因和 Pembrolizumab用于微卫星高不稳定性(MSI-H)或错配修复缺陷实体瘤 现在需要体细胞和生殖系DNA图谱来为晚期男性提供最佳的标准护理 前列腺癌。然而，在BRCA和其他DNA修复途径基因突变的患者中，只有 亚组-充其量只有一半-对批准的靶向治疗有反应。同样，只有一部分MSI-H患者 前列腺癌对培溴利珠单抗有反应。在这个项目中，我们将利用机构规模 前瞻性肿瘤和生殖系测序倡议，以扩大我们对基因组影响的理解 前列腺癌患者对靶向治疗和免疫治疗的临床结果和反应的改变 癌症。我们的首要目标是识别与致命性进展相关的基因组改变。 并改进分子靶向治疗局部晚期和晚期肺癌的方法。 转移性前列腺癌。我们将通过三种广泛的方法实现这些翻译目标： 1)我们将开发最大的临床基因组数据集，包括患有高危、局限性前列腺癌和 在这种疾病状态下，测试基因组改变与临床结果的相关性。复发率 至少40%的高危、临床局限性前列腺癌代表着一个重要的未得到满足的领域 新的治疗方法，包括采用靶向治疗和分子引导治疗 强化治疗，以降低复发风险。2)我们将用DDR鉴定肿瘤的分子特征 比DDR突变状态更能预测对PARP抑制剂敏感性或耐药性的改变 独自一人。更具体地说，我们将使用定向和全基因组测序分析来探索 突变合子、克隆性和结构变异签名的存在与 对PARP抑制剂治疗的反应。3)我们将确定可提起诉讼的DNA修复更改的时间 在前列腺癌疾病进展过程中发生的以及先前存在的、患者内部的异质性对 使用序贯肿瘤和血浆测序对已批准的靶向和免疫治疗的反应。总而言之， 基于我们在临床分子图谱方面的机构专业知识，我们能够产生预期的 数千名接受标准和研究治疗的前列腺癌患者的数据集，以及 我们在推动前列腺癌和其他疾病靶向治疗的临床开发方面的经验 恶性肿瘤，包括领导这项研究，导致FDA首次批准PARP抑制剂用于 前列腺癌，我们处于开发和改进靶向治疗方法的极佳地位，将 有利于患有局部晚期和转移性前列腺癌的男性。

SUMMARY/ABSTRACT Clinical sequencing has only recently begun to inform the selection of FDA-approved therapies for individual patients with prostate cancer. The recent FDA approvals of rucaparib and olaparib for men with metastatic castration-resistant prostate cancers harboring alterations in DNA damage repair (DDR) genes and of pembrolizumab for microsatellite instability–high (MSI-H) or mismatch repair deficient solid tumors dictate that somatic and germline DNA profiling are now required for the optimal standard care of men with advanced prostate cancer. However, among patients with BRCA and other DNA repair pathway gene mutations, only a subset—half at best—respond to approved targeted therapies. Similarly, only a subset of patients with MSI-H prostate cancers will responds to pembrolizumab. In this project, we will leverage an institutional-scale prospective tumor and germline sequencing initiative to expand our understanding of the impact of genomic alterations on clinical outcomes and response to targeted and immune-based therapies in men with prostate cancer. Our overarching aims are to identify genomic alterations associated with progression to the lethal metastatic phenotype and to refine molecularly targeted approaches to the treatment of locally advanced and metastatic prostate cancer. We will accomplish these translational objectives through three broad approaches: 1) We will develop the largest clinical genomic data set of men with high-risk, localized prostate cancer and test the association of genomic alterations with clinical outcomes in this disease state. With a recurrence rate of at least 40%, high-risk, clinically localized prostate cancer represents an area of significant unmet need for novel treatment approaches, including the introduction of targeted therapies and molecularly guided treatment intensification to reduce the risk of recurrence. 2) We will identify molecular features of tumors with DDR alterations that are more predictive of sensitivity or resistance to PARP inhibitors than DDR mutational status alone. More specifically, we will use targeted and whole-genome sequencing analyses to explore the associations between mutational zygosity, clonality, and the presence of structural variant signatures and response to PARP inhibitor therapy. 3) We will determine the timing at which actionable DNA repair alterations arise during prostate cancer disease progression and the impact of preexisting, intrapatient heterogeneity on response to approved targeted and immunotherapies using sequential tumor and plasma sequencing. In sum, on the basis of our institutional expertise in clinical molecular profiling, our ability to generate a prospective data set of thousands of patients with prostate cancer treated with standard and investigational therapies, and our experience in advancing the clinical development of targeted therapies in prostate cancer and other malignancies, including leadership of the study that resulted in the first FDA approval of a PARP inhibitor for prostate cancer, we are in an excellent position to develop and refine targeted treatment approaches that will benefit men with locally advanced and metastatic prostate cancer.