# Investigating CREBBP as a tumor suppressor in small cell lung cancer

> **NIH NIH R01** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2020 · $441,962

## Abstract

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...

## Key facts

- **NIH application ID:** 9825525
- **Project number:** 5R01CA200547-04
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** David MacPherson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $441,962
- **Award type:** 5
- **Project period:** 2016-12-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9825525

## Citation

> US National Institutes of Health, RePORTER application 9825525, Investigating CREBBP as a tumor suppressor in small cell lung cancer (5R01CA200547-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9825525. Licensed CC0.

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