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

项目1：早期检测转移性前列腺癌患者治疗耐药性的非侵入性临床检测

• 批准号: 10227729
• 负责人: Himisha Beltran
• 金额: $ 34.38万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-30 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227729
• 关键词: Affect; Androgen Receptor; Area; Award; BRCA2 gene; Biological Assay; Biological Markers; Biopsy; Blood Circulation; Blood Tests; Cancer Patient; Carcinoma; Castration; Cells; Clinical; Collection; DNA; DNA Methylation; DNA Sequence Alteration; Data; Dependence; Development; Disease; Disease Progression; Dreams; Early Diagnosis; Enrollment; Fanconi Anemia Complementation Group A Protein; Genes; Genomics; Goals; Heterogeneity; Institutional Review Boards; Lead; Letters; Malignant neoplasm of prostate; Medicine; Metastatic Prostate Cancer; Nature; Neuroendocrine Prostate Cancer; Neurosecretory Systems; PTEN gene; Pathologic; Patient Selection; Patients; Pattern; Performance; Pharmaceutical Preparations; Phenotype; Plasma; Platinum; Population; Progression-Free Survivals; Prospective cohort; RB1 gene; Receptor Signaling; Refractory Disease; Resistance; Sampling; Selection for Treatments; Site; Specimen; TP53 gene; Testing; Time; Tissues; Visceral metastasis; Work; abiraterone; advanced disease; advanced prostate cancer; assay development; base; cancer clinical trial; castration resistant prostate cancer; circulating DNA; clinical development; exome sequencing; genomic biomarker; genomic signature; hormone therapy; improved; industry partner; member; neuroendocrine phenotype; patient subsets; predicting response; prognostic; prospective; receptor expression; safe patient; targeted treatment; therapy resistant; transcriptome; tumor

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.

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。