Molecular Drivers and Therapeutic Susceptibilities in Neuroendocrine Prostate Cancer

PROJECT SUMMARY/ABSTRACT – PROJECT 3 Prostate cancer (PC) is the second-leading cause of cancer mortality among men in the United States. While the majority of patients can be cured with initial therapy, lethal castration-resistant prostate cancer (CRPC) occurs through resistance to androgen deprivation therapy (ADT). ADT resistance can occur from lineage plasticity, a process where androgen receptor (AR)-dependent prostate adenocarcinomas switch to AR- independent phenotypes, such as treatment-emergent neuroendocrine prostate cancer (t-NEPC). Up to 17% of CRPC patients have histologically discernable t-NEPC on biopsies, and these patients have significantly worse outcomes compared to non-t-NEPC patients. Treatment approaches for t-NEPC patients are limited. Given the need to better understand, define, and treat t-NEPC, we now propose to investigate molecular events that drive t-NEPC, to define how t-NEPC shapes its surrounding tumor microenvironment (and vice versa), and to develop blood-based non-invasive biomarkers to detect t-NEPC. These goals will be achieved via three aims: Specific Aim 1: To identify molecular drivers that promote t-NEPC, we will perform a perturb-seq CRISPRa screen in prostate cancer cells with inactivated TP53 and RB1 to identify the drivers of lineage plasticity that promote t-NEPC in mCRPC patients. We will then validate these findings in novel models of prostate cancer derived from induced pluripotent stem cells (iPSCs) and assess the impact of targeting these candidate factors in mouse models of t-NEPC. Specific Aim 2: t-NEPC has unique tropism to the liver, but it is unknown why this tropism exists. Using a unique microscale and microfluidic technology, we will define the molecular phenotype and sensitivity of t-NEPC cells in 3D culture, show how the tumor microenvironment of the liver promotes t-NEPC growth and expression of targetable surface proteins, and define how t-NEPC cells drive key immune cell subtypes to promote tumor growth and therapy resistance. Execution of Aim 2 will enable mechanistic dissection of the interaction between t-NEPC tumor cells and the TME, and will identify potential therapeutic targets linked to this interaction. Specific Aim 3: To enable development of an optimized non-invasive biomarker panel for t-NEPC, we will optimize a ctDNA-based biomarker panel for t-NEPC, assess the association between ctDNA-based t-NEPC biomarkers and progression on ARPIs in data from four phase III registration trials, and determine how t-NEPC biomarkers change after progression. There is a clear need to better understand the drivers of t-NEPC and to improve management for patients with this disease. Successful completion of our proposed aims will help define the molecular pathogenesis of t- NEPC, identify potential therapeutic targets for this disease entity, and help develop a biomarker strategy for selecting t-NEPC patients to trial.