Project 3 - INSM1, A Candidate Therapeutic Target in High-Grade Neuroendocrine Carcinomas

Project Summary/Abstract (Project 3) Small cell lung cancer (SCLC), Merkel cell carcinoma (MCC), and neuroendocrine prostate cancer (NEPC) are aggressive high-grade neuroendocrine carcinomas (HGNCs) with no approved targeted therapies. These HGNCs highly express lineage-specific neuroendocrine transcription factors (NETFs) that promote neuroendocrine differentiation and sustain their survival presenting a potential opportunity to target NETFs in HGNCs. INSM1 is a C2H2-type zinc-finger transcriptional repressor that normally functions to control endocrine differentiation during islet cell development of the pancreas. In contrast to the other NETFs which are only expressed in subsets of HGNCs, INSM1 is more universally expressed across HGNCs and is commonly used as a clinical biomarker for the pathological diagnosis of HGNCs. INSM1 is also unique in that it is a C2H2-type zinc-finger transcription factor that shares homology with the druggable IKZF C2H2-type zinc-finger transcription factor family that can be targeted by immunomodulatory (iMiDs) drugs such as lenalidomide. Our preliminary data suggests that INSM1 is critical for survival and neuroendocrine differentiation in these three HGNCs. We hypothesize that INSM1 is a therapeutic target for HGNCs and is druggable with iMiD small molecules. To test this hypothesis, we will investigate the mechanistic role of INSM1 in controlling neuroendocrine differentiation and survival in HGNCs using both genetic and pharmacological approaches in a variety of pre-clinical models of SCLC, NEPC and MCC (Aim 1). We will utilize xenograft and patient-derived xenograft models to determine if INSM1 is required for tumor maintenance in HGNCs (Aim 2). We have identified mechanisms by which HGNCs normally degrade INSM1 protein and we will further investigate these mechanisms in the first part of aim 3. Moreover, we performed an iMiD-derivative small molecule library screen and identified 3 lead iMiD compounds that degrade INSM1. We will further test whether these iMiDs directly bind and degrade INSM1 and their selectivity for INSM1 in the second part of aim 3. This project is built upon compelling preclinical data by the project leaders in all three HGNCs and leverages their distinct expertise and unique preclinical models of HGNCs. Successful completion of this project will lead to an enhanced mechanistic understanding of how INSM1 controls the neuroendocrine phenotype and proliferation of HGNCs, determine whether INSM1 inhibition by targeted protein degradation has therapeutic efficacy in HGNC, and will identify small molecule iMiDs that can bind and degrade INSM1 as a novel therapeutic strategy for HGNCs.