The Molecular Drivers and Therapeutic Susceptibilities in Lineage State Transitions of Metastatic Prostate Cancer

University Of Wisconsin-Madison, Madison WI

Investigators

Abstract

OVERALL PROGRAM 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). Despite these advances, median survival 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 >95% of patients. Molecular analysis of tissue biopsies has the development of phenotypic alterations indicative of neuroendocrine prostate cancer (NEPC). These observations gave rise to the concept of “Lineage Plasticity” wherein PC, under the selective pressure of ARPIs, can undergo lineage transitions to developmental cellular prostate subtypes as a driver of resistance. However, many patients retain androgen receptor positive prostate cancer (ARPC) or even the absence of either histologic subtype (Double- negative prostate cancer or DNPC). Genomic mutations in p53 and RB associate with lineage plasticity, as well as PC invasion of different metastatic niches, such as liver and bone. However, these alterations are not exclusive to NEPC and do not explain the molecular triggers of lineage transitions. New technological innovations and biologic discoveries in our respective laboratories strongly support the overarching hypothesis that early molecular events promote lineage transitions in metastatic niches that culminate in lethal tumor phenotypes and offer new opportunities for diagnostic and therapeutic intervention. To address this hypothesis, project aims are: Project 1: Lineage Addiction in Prostate Cancer: Molecular Interactions and Translational Biomarkers. This project will study the luminal CRPC state that retains androgen dependence but is resistant to ARPIs. They will evaluate how the AR transcriptional state is regulated in distinct tumor niches, with AR mutations alone or in combination with other high-risk mutations, to promote treatment resistance. They will explore new therapeutic sensitivities and treatment combinations across distinct niches and translational biomarkers in clinical studies. Project 2: Molecular Transitions Driving AR Loss in Double Negative Prostate Cancer. This project evaluates the genetic and epigenetic alterations that lead to the DNPC lineage that is independent of androgen signaling for proliferation and invasion. They will explore why the liver metastatic niche is enriched for this unique lineage and identify biomarkers that will be studied in two prospective clinical studies. Project 3. Molecular Drivers and Therapeutic Susceptibilities in Neuroendocrine Prostate Cancer. This project builds on data from the investigative team on the terminal NEPC differentiation state that drives a rapidly proliferative disease that responds only to chemotherapy. Using perturb-seq CRISPR screens for high-risk genomic mutations, they will uncover the drivers of neuroendocrine transformation and biomarkers that will be evaluated in samples from multiple randomized clinical trials.