Molecular regulation and expression of Trop-2 in advanced prostate cancer: Identifying optimal therapeutic niches

PROJECT SUMMARY/ABSTRACT The last decade has seen a significant increase in the number of FDA approved treatments for men with metastatic castrate resistant prostate cancer (mCRPC). Even greater improvements in survival were observed for men with metastatic castration sensitive PC (mCSPC) treated with chemotherapy or androgen receptor signaling inhibitors compared to hormone therapy alone (Despite these advances in mCSPC, median OS for men with mCRPC remains less than two years and cross-resistance to therapies within the same class (e.g. Enzalutamide and Abiraterone) occurs in >90% of patients, limiting effective treatments in mCRPC to agents with OS improvements ranging from only 2-4 months. There is a critical need to identify new agents that can eliminate resistant disease5. Understanding the molecular associations driving resistance may identify new therapeutic sensitivities in these aggressive cancers to improve quality and quantity of life for men with mCRPC. Translational research studies focused on understanding the underlying mechanisms driving treatment resistance in CRPC have identified a wide range of genomic, epigenomic and transcriptional alterations. Approximately 15-20% of patients with mCRPC develop lineage plasticity, with small cell neuroendocrine CRPC (SCNPC) representing the most aggressive subtype. However, the field lacks consensus definitions for the diverse lineage plasticity phenotypes observed in mCRPC, and few therapeutic targets have been developed to date. In this study, we propose Trop-2 (Trophoblastic cell-surface antigen) as a high value target for therapy of mCRPC with an antibody-drug conjugate Sacituzumab Govitecan (SG). We hypothesize that ARSI-resistant phenotypes in mCRPC can be identified through integrated solid tumor and liquid biopsy analysis and targeted therapeutically with SG. To test this hypothesis, we propose to study Trop-2 regulation in pre-clinical and clinical specimens and test this agent in a prospective Phase II clinical trial for ARSI-resistant mCRPC. In Aim 1, we will conduct molecular-spatial analysis of Trop-2 expression in mCRPC PDX tissues as well as solid tumor and liquid biopsies from patients with CSPC, CRPC and SCNPC In Aim 2, we will evaluate solid tumor and liquid biopsies collected longitudinally from patients with mCRPC treated with SG in a prospective Phase II trial. Aim 2 will characterize chromatin enhancer profiles in the TACSTD2 gene encoding Trop-2 to identify factors regulating Trop-2 levels in prostate cancer. We will test if Trop-2 levels determine sensitivity to SG therapy, and identify SG-based combination regimens that enhance therapeutic efficacy in vitro and in vivo.