Convergent Epigenetic Control of Neuroendocrine Cancers

Summary (Overall) The overall goal of the Program “Convergent Epigenetic Control of Diverse Neuroendocrine Cancers” is to interrogate epigenetic and transcriptional states that are required for the development of neuroendocrine (NE) cancers. We propose to study NE cancers in four tissue types to test the hypothesis that the NE phenotype is dependent on a common set of transcription factors and epigenetic regulators that control gene expression patterns and creates vulnerabilities that provide opportunities for the identification and validation of new targets for therapeutics. To accomplish this goal, we will study small intestinal neuroendocrine tumors (SI-NET) tumors, neuroendocrine prostate cancer (NEPC), small cell lung cancer (SCLC), and cutaneous Merkel cell carcinoma (MCC). We propose that the integrated study of this diverse set of NE cancers will provide a deeper understanding of the mechanisms for NE transformation, including the propensity for lineage plasticity as well as therapeutic strategies to improve responses to targeted and immune therapy. The Program Project has three Projects plus an Epigenomics Core utilized by all three Projects and is coordinated by an Administrative Core. Each Project is led by two co-Leaders that will facilitate interactions across the Program. Each Project and Core specifies a Specific Aim of the Program. Project 1, “Epigenetic Control of Normal and Malignant Neuroendocrine Differentiation”, is co-led by Ramesh Shivdasani and Myles Brown. Project 1 aims to define the transcriptional and epigenetic basis of human intestinal NE differentiation and then examine how this molecular understanding might inform therapeutic approaches toward castration-resistant NEPC. Project 2, “Epigenetic Drivers of Lineage Plasticity in Lung Cancer” is co-led by Matthew Oser and David Barbie. Through studying EED inactivation in SCLC in immunocompetent tumor microenvironment, we will identify the epigenetic mechanisms that promote histological lineage plasticity. Project 3, “INSM1, A Candidate Therapeutic Target in High-Grade Neuroendocrine Carcinomas”, is co-led by James DeCaprio and Matthew Oser. Project 3 will determine if INSM1 can serve as therapeutic target in high grade NE carcinomas and identify iMiDs that degrade INSM1. The Epigenomics Core will provide bioinformatic analysis and integration of the data derived from the molecular profiling experiments proposed. The Administrative Core, led by James DeCaprio, will work to ensure continued focus on deciphering the Convergent Epigenetic Control of Diverse Neuroendocrine Cancers.