Project 1: Non-Invasive Clinical Assay for Early Detection of Treatment Resistance in Patients with Metastatic Prostate Cancer

总结 确定不再受益于前列腺癌治疗的转移性去势抵抗性前列腺癌（CRPC）患者 有效的雄激素受体（AR）导向疗法是一种未满足的需求。一种机制涉及AR的丢失 信号依赖性及其早期检测仍然具有挑战性。我们开发了一种基因组特征 与AR独立性和可以非侵入性检测的神经内分泌表型相关 使用病人的血浆样本。在这项提案中，我们将开发一种靶向检测方法， 队列，以评估肿瘤动力学和AR非依赖性基因组改变在预测 对后续AR靶向治疗的反应。我们还将定义循环的频谱和模式， 使用全外显子组比较转移性CRPC患者的肿瘤克隆与匹配活检 排序方法。这项研究将导致血浆基因组生物标志物的进一步临床开发 有几个潜在的影响领域，包括早期发现向AR转化的患者， 独立性导致早期停止AR治疗，并考虑转移性活检以寻找 神经内分泌转化和基于铂的疗法。

SUMMARY Identifying patients with metastatic castration resistant prostate cancer (CRPC) that will no longer benefit from potent androgen receptor (AR)-directed therapies is an unmet need. One mechanism involves loss of AR signaling dependence and its early detection remains challenging. We have developed a genomic signature associated with AR-independence and the neuroendocrine phenotype that can be detected non-invasively using plasma samples from patients. In this proposal, we will develop a targeted assay applied to prospective cohorts to assess tumor dynamics and clinical impact of AR-independent genomic alterations in predicting response to subsequent AR-targeted therapies. We will also define the spectrum and pattern of circulating tumor clones compared to matched biopsies in patients with metastatic CRPC using a whole exome sequencing approach. This study would lead to further clinical development of a plasma genomic biomarker with several areas of potential impact including early detection of patients transforming towards AR- independence leading to early cessation of AR therapy and consideration of metastatic biopsy to look for neuroendocrine transformation and platinum-based therapies.