Research Project 1: Understanding the Molecular Evolution of Castration-Resistant Prostate Cancer

项目总结/摘要 在合理设计治疗方法的努力的催化下，基因组导向肿瘤学的时代已经到来 靶向促进个体肿瘤生长和进展的分子畸变。这导致 对活动性疾病患者进行前瞻性临床测序，以指导他们的癌症护理。但 这种前瞻性分析的效用在许多癌症类型中是有限的，也许在患有前列腺癌的男性中最是如此。 癌事实上，部分由于它们深刻的临床和突变异质性，我们对它们知之甚少。 如何治疗靶向基因组中的分子损伤，这些损伤导致了最严重的 侵袭性转移性去势抵抗性前列腺癌（CRPC）。我们必须应对这一紧迫挑战， 提高CRPC患者的生存率。我们最近表明， 与临床注释相关的活动性晚期前列腺癌可以揭示基因和途径水平 CRPC中富集的基因组畸变。我们继续表明，生殖细胞和体细胞病变都是针对 介导同源重组（HR）的基因在CRPC中远比在晚期CRPC中更常见。 去势敏感性转移这些研究结果强调了定义这些疾病的潜在治疗效用。 病变驱动CRPC，但没有临床转化的方法，测试这些假设临床， 我们理解上的差距只会越来越大。我们建议首先克服这一紧迫的临床挑战， 开发并全面分析了一个由大约2,000名测序的高级 来自积极治疗患者的前列腺癌，详细的临床注释、结局和治疗- 响应数据。这项工作的一个主要目标是确定与进展相关的改变， 去势抵抗，这将有助于测试新的方法来治疗这种肿瘤的策略。我们将 然后评估基因组杂合性丢失和HR缺陷相关标志的程度 与不同的潜在体细胞或生殖系HR/DNA修复基因型，特定的临床变量， 疾病特异性进展和结果。最后，我们将在临床上检验CRPC患者 具有HR功能障碍的标志，包括具有生殖系或体细胞BRCA突变的患者， PARP抑制的临床获益。我们还将寻求确定基因组畸变的条件PARP 治疗前和治疗后样品以及纵向收集的肿瘤中的抑制剂应答和抗性， 衍生的无细胞DNA。总之，这些研究试图建立一个翻译基因组框架，以促进 通过有效靶向基本途径， 导致疾病进展到晚期。

PROJECT SUMMARY/ABSTRACT An age of genomically directed oncology has arrived, catalyzed by efforts to rationally design therapies targeting the molecular aberrations that promote individual tumor growth and progression. This has led to the prospective clinical sequencing of patients with active disease to guide their cancer care. Nevertheless, the utility of such prospective profiling is limited in many cancer types, perhaps most so in men with prostate cancer. In fact, due in part to their profound clinical and mutational heterogeneity, we know very little about how to therapeutically target the molecular lesions in the genomes that drive the emergence of the most aggressive metastatic castration-resistant prostate cancers (CRPC). We must address this urgent challenge to improve the survival of men with CRPC. We have recently shown that prospective clinical sequencing of active, advanced prostate cancers with linked clinical annotation can reveal both gene- and pathway-level genomic aberrations enriched in CRPC. We went on to show that both germline and somatic lesions targeting genes mediating homologous recombination (HR) were far more common in CRPC than even advanced castration-sensitive metastases. These findings underscore the potential therapeutic utility of defining the lesions that drive CRPC, but without a clinical-translational approach that tests these hypotheses clinically, the gap in our understanding will only widen. We propose to overcome this urgent clinical challenge by first developing and comprehensively analyzing a one-of-kind cohort of approximately 2,000 sequenced advanced prostate cancers from patients under active care with detailed clinical annotation, outcome, and treatment- response data. A major goal of this effort will be to identify alterations associated with progression to castration-resistance, a strategy that will facilitate the testing of novel approaches to treat such tumors. We will then assess the extent to which genomic loss of heterozygosity and related hallmarks of HR deficiency are correlated with different underlying somatic or germline HR/DNA repair genotypes, specific clinical variables, disease-specific progression, and outcome. Finally, we will clinically test the hypothesis that men with CRPCs bearing the hallmark of HR dysfunction, including those with germline or somatic BRCA mutations, derive clinical benefit from PARP inhibition. We will also seek to identify genomic aberrations that condition PARP inhibitor response and resistance in pre- and post-treatment samples and longitudinally collected tumor- derived cell-free DNA. Together, these studies seek to establish a translational genomic framework to facilitate effective, evidence-based precision oncology in men with CRPC by efficiently targeting essential pathways that drive the progression to advanced disease.