# Targeting Multiple Colorectal Cancer-Specific Enhancers

> **NIH NIH R21** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $234,378

## Abstract

PROJECT SUMMARY/ ABSTRACT
Many genes required for cancer formation also perform essential functions in normal cells. Elimination of such
genes would, therefore, likely evoke unfortunate side effects on normal cells. Recent developments in the field
of gene regulation suggest a possible solution to this problem. Transcription is typically activated by
enhancers, regulatory DNA elements bearing a group of bound transcriptional activators. An enhancer can
extend over many hundreds of base pairs, and is often positioned hundreds or even thousands of base pairs
from its target gene. A given gene is typically driven by an enhancer in one cell type, and by a different
enhancer (comprising different transcription factors, bound at a different DNA location) in other cell types. We
and others have described enhancers of oncogenes in tumor cells that are not found in normal cell s. Were we
to inactivate or eliminate such tumor-specific enhancers (while not damaging enhancer formation in their non-
tumor counterparts), we would inhibit tumor cell growth without affecting growth or function of normal cells.
Three recent developments have suggested a path to identifying and inactivating specific enhancers. First, we
and others have developed assays that identify enhancers genome-wide in tumors and in normal cells.
Second, recent developments in CRISPR technology have suggested a means by which we can
simultaneously eliminate (destroy) multiple independent enhancers. Third, methods have been developed to
grow organoids, groups of cells that more closely mimic cells (normal and tumor) in vivo than previously
described procedures. Key personnel on this application, Dr. Scott Lowe at Memorial Sloan Kettering Cancer
Center (MSKCC), has made seminal advances in modeling cancer, using organoids. Our co -PI, Dr. Michael
Roehrl at MSKCC, is a recognized physician-scientist and pathologist with special expertise in colorectal
cancers (CRCs). Additional key personnel, serving as contributors, such as Dr. Christina Leslie also at
MSKCC, is an expert in computational biology and will assist us in data analysis.
We will identify CRC-specific enhancers in CRC tumors and organoids derived therefrom. We will apply
CRISPR technology to identify which of the genes activated by these enhancers, in pairs, are required for
growth of CRC organoids. We will then use CRISPR tiling mutagenesis to identify enhancer sequences
required for expression of these genes. From this knowledge, we will design pairs of guide RNAs that, by
simultaneously attacking crucial enhancers, will specifically inhibit CRC organoid formation.

## Key facts

- **NIH application ID:** 9894773
- **Project number:** 5R21CA231109-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** MARK S PTASHNE
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $234,378
- **Award type:** 5
- **Project period:** 2019-03-15 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9894773

## Citation

> US National Institutes of Health, RePORTER application 9894773, Targeting Multiple Colorectal Cancer-Specific Enhancers (5R21CA231109-02). Retrieved via AI Analytics 2026-05-31 from https://api.ai-analytics.org/grant/nih/9894773. Licensed CC0.

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