# Chromatin Modifier Gene Mutation and Enhancer Dysfunction in Bladder Cancer

> **NIH NIH K08** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $243,205

## Abstract

Project Summary and Abstract
The overall goal of this proposal is to support the training of Dr. Byron Lee to become an independent investigator
conducting translational research in bladder cancer epigenomics. Dr. Lee will be mentored by Dr. Nima Sharifi
and Dr. Peter Scacheri. Dr. Nima Sharifi is the leader of the Genitourinary Malignancies Program at the Case
Comprehensive Cancer Center and has mentored numerous young physician-scientists. Dr. Peter Scacheri is
Professor of Genetics at Case Western Reserve University and an expert in cancer epigenomics. The training
plan incorporates the following goals: (1) enhance understanding of chromatin biology, (2) gain expertise in
bioinformatics analysis of complex biological data, and (3) develop proficiency in the use of patient-derived
samples for translational research. Bladder cancer is the fifth most common non-cutaneous malignancy in the
United States, yet few new treatment options exist. The Cancer Genome Atlas (TCGA), a large-scale effort
supported by NCI and NHGRI to determine the molecular basis of cancer, performed comprehensive molecular
characterization of over 400 muscle invasive bladder cancers and showed that chromatin modifier gene
alterations occur in 75% of cases. Most of these alterations are predicted to result in loss of function; however,
their effects on bladder cancer initiation, progression, and response to therapy are largely unknown. These genes
alter the configuration of the DNA-histone interface, which affects the ability of DNA-binding proteins to access
their target sequences. The central hypothesis that will be tested is that chromatin modifier gene mutation leads
to gene expression changes that support bladder cancer initiation and progression through enhancer disruption.
To accomplish this goal, we propose the following Specific Aims: (1) Test the hypothesis that KDM6A inactivation
alters the chromatin state of urothelial cells and engenders a transcriptional program that results in neoplastic
growth, and (2) Test the hypothesis that enhancer dysfunction and aberrant transcriptional circuits characterize
human bladder cancer and dependence on these circuits for growth result in vulnerability to existing targeted
therapies. Successful completion of the proposed research will advance our understanding of how chromatin
modifier gene mutations, one of the most frequent somatic alterations in bladder cancer, affect disease initiation
and progression. Moreover, we expect to identify molecular vulnerabilities arising from enhancer disruption and
changes in transcription factor circuits. Targeting these vulnerabilities can lead to the development of novel
therapies for bladder cancer.

## Key facts

- **NIH application ID:** 9881272
- **Project number:** 5K08CA237842-02
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Byron H Lee
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $243,205
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9881272

## Citation

> US National Institutes of Health, RePORTER application 9881272, Chromatin Modifier Gene Mutation and Enhancer Dysfunction in Bladder Cancer (5K08CA237842-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9881272. Licensed CC0.

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