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

基本信息

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
项目类别：
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

项目摘要

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.

概括确定将不再受益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）导向疗法是一个未得到满足的需求。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。我们开发了基因组特征与 AR 独立性和可非侵入性检测的神经内分泌表型相关使用患者的血浆样本。在本提案中，我们将开发一种靶向检测方法，应用于前瞻性研究队列评估肿瘤动力学和 AR 独立基因组改变对预测的临床影响对后续 AR 靶向治疗的反应。我们还将定义流通的范围和模式使用全外显子组对转移性 CRPC 患者的肿瘤克隆与匹配活检进行比较测序方法。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具有多个潜在影响领域，包括及早发现向 AR 转变的患者独立性导致早期停止 AR 治疗并考虑进行转移性活检以寻找神经内分泌转化和铂类疗法。