Identifying mechanisms of initiation and maintenance of neuroendocrine prostate cancer

Abstract

Small cell or neuroendocrine prostate cancer (SCNPC) is a rare but aggressive subtype of prostate cancer with no FDA-approved targeted therapies. SCNPC is an androgen-receptor independent subtype that often emerges as foci within conventional androgen-receptor dependent prostate cancers (ARPCs) that have undergone androgen-deprivation therapy (ADT). SCNPC and ARPC have highly similar mutational landscapes (including fusions in AR-regulated genes) but display distinct transcriptional programs. Investigations into the molecular mechanisms that are responsible for the development and maintenance of the neuroendocrine phenotype in prostate cancer have been hindered due to the scarcity of tumors and a lack of model systems with which to study the subtype. Small cell or neuroendocrine tumors (SCNTs) arise in many organ sites throughout the body and have similar expression patterns of marker genes used to identify and diagnose this class of tumors, including chromogranins and synaptophysins. In the following thesis, I conducted a transcriptome-wide comparison of SCNTs from different organ sites in order to identify related features. I found similar expression in thousands of genes among SCNTs, including transcription factors that may orchestrate the development of neuroendocrine gene expression programs and their downstream effectors, some of which may present as attractive therapeutic targets. I next evaluated the therapeutic efficacy of inhibiting two such targets using in vitro and in vivo models of SCNPC. Finally, I examined the role of the highly expressed SCNT-associated transcription factor, Insulinoma associated 1 (INSM1), in the development of the neuroendocrine phenotype in prostate cancer. Together this work provides novel insight into the molecular mechanisms that promote the initiation and maintenance of SCNPC.