Chemokine Signaling And Mapk/Erk Pathway For Advanced Prostate Cancer Treatment Response

TPS275 Background: Androgen deprivation therapy (ADT) is the backbone of therapy for metastatic hormone sensitive prostate cancer (mHSPC). Despite a high response rate, the majority of patients progress to metastatic castration-resistant prostate cancer (mCRPC). Both disease settings are heterogeneous with variable responses to treatment. While prostate specific antigen is an important biomarker for prognosis and disease monitoring, it has limitations. Biomarkers predictive of disease response and progression are critically needed. Circulating tumor cells (CTCs) are shed from tumors and are found in blood during advanced stages of disease. Serial characterization of CTCs serves as a real-time ‘liquid biopsy’ for molecular profiling of PC. Recent reports suggest that phenotypic & genomic heterogeneity in CTCs and cell-free DNA (cfDNA) is associated with response to AR-targeted therapy highlighting the importance of CTC as a predictive biomarker. In addition, there is a high concordance between mutations in CTCs’ DNA and CRPC tissue through whole cell exome sequencing. We showed that atypical chemokine receptor CXCR7 is up-regulated following AR-targeted therapies, activating MAPK/ERK signaling and resulting in treatment resistance (Li et al., Cancer Res. 2019). To examine the potential of CXCR7/MAPK/ERK signaling in predicting treatment response, we propose to evaluate MAPK/ERK gene signature, pERK and AR level in CRPC or mHSPC patients receiving systemic therapy. Methods: Men with new CRPC or mHSPC are eligible prior to initiating new therapy for the respective disease setting of ADT + AR targeted therapy or chemotherapy. For CRPC arm, we will collect samples at baseline, 3, 6 months & at time of progression. For mHSPC arm, samples are collected at baseline, after 7 months & at progression. We will enroll 120 patients. Collected samples are subjected to identification, isolation, and enumeration of CTCs. Our primary molecular testing will include AR and pERK staining. CfDNA exome and methylome analysis will be performed to evaluate genomic heterogeneity and epigenomic alterations. We will explore pairwise association among biomarkers of interest, stratified by subgroups, using measures of association.