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.
One emerging mechanism of treatment resistance affecting a subset of patients with advanced prostate cancer is the development of a neuroendocrine phenotype associated with aggressive disease and Androgen Receptor (AR) signaling independence. Metastatic biopsies to look for this resistance phenotype are not often feasible or safe. Successful completion of this project will directly lead to a non-invasive biomarker assay (blood test) for further clinical development with a goal of ultimately improving earlier detection of patients unlikely to benefit from additional AR-targeted strategies and selection of patients for platinum or other neuroendocrine-directed therapies. ! !
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