PROJECT SUMMARY/ABSTRACT
Prostate cancer (PCa) is the second leading cause of cancer related death in American men. Typically,
treatment for PCa involves blocking androgen synthesis or androgen receptor (AR) signaling known as
androgen deprivation therapy (ADT). Although initial response rates are promising, all men eventually progress
on ADT and develop castration resistant prostate cancer (CRPC) concomitant with metastatic burden.
Metastatic CRPC is incurable and an increasing number of men are developing a highly lethal variant of CRPC
known as aggressive variant prostate cancer (AVPC). AR signaling is lost in AVPC rendering the existing
hormone targeting treatments ineffective. About a third of AVPC tumors also express neuroendocrine (NE)
genes and are classified as neuroendocrine prostate cancer (NEPC), which is the focus of our studies. Very
few therapies exist and only offer minimal survival benefits in this setting. Hence, functional assessment of
other protein drug targets is needed to effectively treat NEPC. We have previously shown that kinase signaling
pathways may be promising therapeutic alternatives in CRPC. The goal of our research is to understand the
mechanisms regulating increased kinase gene expression, leading to kinase pathway activation, and how to
effectively target these kinases in NEPC. Our hypothesis is that RET mRNA and protein up-regulation is driven
by ASCL1, a master neural transcriptional regulator, and that RET kinase-mediated activity serves as a
therapeutic vulnerability in NEPC. It is known that RET mutations are key drivers and therapeutic targets in
other cancers with NE features such as papillary thyroid carcinoma and small cell lung cancer. Importantly, the
contribution of RET kinase signaling in NEPC viability is not entirely elucidated. Our preliminary data shows
that RET kinase is overexpressed via activation of a neuronal differentiation transcription factor, ASCL1, and
enzymatically activated in mouse models and organoids of NEPC, in human cell lines, and clinical NEPC
tumors. Our work also shows that RET kinase inhibition reduces in vivo xenograft tumor growth and in in vitro
mouse organoid models of NEPC. The goals of this project are to: 1) confirm ASCL1 as a direct transcriptional
regulator of RET, 2) define a RET activity signature and assess the association of this signature to treatment
resistance and NEPC in clinical samples, and 3) optimize co-targeting strategies with novel RET inhibitors in
NEPC model systems. These goals are collectively designed to investigate the mechanism of RET kinase as a
key therapeutic target in NEPC, an incurable variant of PCa. While kinase inhibitors are approved for treatment
of several epithelial cancers, clinical trials of kinase inhibitors in PCa have been disappointing. Our data
indicate this is likely due to lack of appropriate patient stratification, administered in the wrong clinical context,
and improper combination therapies. Hence, the outcomes of the proposed work will provide new insights into
select combination therapies for treating NEPC, using re-purposed kinase inhibitors that may be implemented
quickly in clinical trials of patients with this subset of lethal PCa.