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

摘要 确定转移性去势抵抗前列腺癌(CRPC)患者将不再受益于 有效的雄激素受体(AR)导向疗法是一个尚未得到满足的需求。一种机制涉及AR的损失 信号依赖及其早期检测仍然具有挑战性。我们已经开发出一种基因组签名 与AR非依赖性和可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，我们将开发一种应用于预期的靶向分析 评估肿瘤动力学和AR非依赖性基因组改变对临床影响的队列预测 对随后的AR靶向治疗的反应。我们还将定义循环的频谱和模式 使用完整外显子组的转移性CRPC患者的肿瘤克隆与匹配活检的比较 排序方法。这项研究将导致血浆基因组生物标记物的进一步临床开发。 有几个潜在的影响领域，包括及早发现患者向AR转变- 独立性导致AR治疗提前停止，并考虑转移性活检寻找 神经内分泌转化和以铂为基础的治疗。

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.