Summary Small cell lung cancer (SCLC) is a neuroendocrine cancer of the lung with dismal survival rates. There are no therapies for SCLC directed towards tumors harboring specific driver mutations. Recent genomic analyses and our own preliminary data revealed that CREBBP mutation/deletion is frequent in human SCLC. CREBBP is an acetyltransferase that acetylates histones and other proteins. CREBBP is emerging as a frequently mutated gene in hematopoietic tumors as well as certain solid tumors, but functional evidence of CREBBP tumor suppressor activity in solid tumors is lacking. We have evidence that CREBBP functions as a critical tumor suppressor gene across multiple neuroendocrine tumor types including SCLC. Our aims are to identify the mechanisms through which CREBBP suppresses SCLC and to test a therapeutic approach directed towards CREBBP-mutant SCLC. Specific Aim 1: To characterize effects of CREBBP deletion in a mouse model of small cell lung cancer and in human cell lines. We will inactivate Crebbp using a sensitized mouse model of SCLC that is driven by lung specific deletions in Rb and p53. In this mouse model, tumors arise with long latency, providing an ideal system to test the ability of potential SCLC driver mutations to accelerate tumorigenesis. Specific Aim 2: To identify mechanisms through which CREBBP deletion collaborates with Rb and p53 loss to promote SCLC. We hypothesize that Crebbp loss collaborates with Rb and p53 loss to promote neuroendocrine tumor types through control of gene expression. By integrating transcriptional data from Crebbp wild-type vs. mutant murine neuroendocrine pituitary tumors, thyroid tumors and SCLC, we will identify a common group of Crebbp-controlled genes across multiple Rb/p53-deleted neuroendocrine tumors. Focusing on SCLC, we will also identify genomic sites with reduced histone acetylation and proteins with reduced acetylation upon CREBBP deletion. Functional experiments will interrogate candidate CREBBP effectors for tumor suppressive activity. Specific Aim 3: To determine whether Crebbp-mutant tumors exhibit sensitivity to HDAC inhibition. We hypothesize that CREBBP deficiency will result in sensitivity to histone deacetylase (HDAC) inhibition as this could potentially restore lost histone acetylation. We will determine whether HDAC inhibition will lead to regression of Crebbp-mutant neuroendocrine tumors employing both genetically engineered and patient derived xenograft models. CREBBP is emerging as a frequently mutated gene in many solid tumors and is one of the most frequently mutated genes in SCLC, but there is a poor understanding of how CREBBP functions as a tumor suppressor. Through integrative analyses of genomic data we will identify Crebbp-controlled tumor suppressive signaling networks. We will also determine whether inactivation of Crebbp leads to sensitivity to the HDAC inhibitor romidepsin. As romidepsin is an FDA- approved drug, positive results could rapidly be translated to improving therapies for patients with CREBBP- mutated tumors.