# Investigating the role of EZH2 as a therapeutic target in colorectal cancers

> **NIH NIH F31** · HARVARD MEDICAL SCHOOL · 2022 · $34,515

## Abstract

Abstract
The Polycomb Repressive Complex 2 (PRC2) is a highly conserved developmental regulator that maintains
cellular identity by dynamically silencing key genes involved in differentiation. Alterations in EZH2, the catalytic
methyltransferase, have been shown to play a driving role in many cancers. Activating mutations in EZH2 have
been detected in a subset of cancers, such as melanoma and lymphomas. However, in most solid tumors, EZH2
is more commonly overexpressed. EZH2 expression levels progressively increase in advanced tumors, and has
been functionally shown to drive prostate cancer metastasis. Nevertheless, the role of EZH2 in other solid
tumors, including colorectal cancers (CRC) has not been sufficiently explored. Specifically, EZH2 is
overexpressed in 78.5% of CRC, and its expression appears to inversely correlate with patient survival. We
hypothesized that EZH2 could be an attractive therapeutic target, although its role and targets in CRC are
unknown. CRC is the is one of the leading causes of cancer deaths worldwide, and advanced metastatic disease
is still incurable. Thus, there is a significant unmet clinical need for treatments for CRC, especially those with
activating mutations in KRAS. Many drugs that target classic oncogenic kinases are ineffective therapies as
single agents, such as MEK inhibitors for KRAS mutant solid tumors. Therefore, one approach has been to
develop more effective combination therapies that might enhance the sensitivity of cells to MEK inhibitors and/or
prevent resistance. In a series of studies, our lab began exploring EZH2 inhibitor-based combination therapies
in a variety of solid tumors. Interestingly, we have found that EZH2 inhibitors are frequently effective when
combined with agents that target other key oncogenic pathways in a given tumor type, such as in breast and
prostate cancer. We hypothesize that co-targeting EZH2 along with key oncogenic pathways may lead to
cooperative killing of CRC cells by clamping down on crucial oncogenic signals at both the kinase level and the
transcriptional level. My preliminary data demonstrate that a combination of EZH2 and MEK inhibitors cooperate
to kill KRAS mutant CRC, which reveal a novel approach for treating this advanced disease. I propose to address
several essential open-ended questions before translating a combination therapy into the clinic, such as the
mechanism of action, the cell intrinsic factors that render tumors responsive to treatment, and whether the drug
combination works in an in vivo preclinical and biologically relevant setting. In Aim 1, I propose to identify putative
biomarkers that dictate sensitivity to EZH2/MEK inhibitors by conducting genomic analyses between sensitive
and resistant cell lines. In Aim 2, I will elucidate the mechanism of action by obtaining a global view of chromatin
and gene regulation, and I will identify critical PRC2 target genes that modulated in CRC after combination
treatment. In Aim 3, I will test the eff...

## Key facts

- **NIH application ID:** 10362561
- **Project number:** 5F31CA260804-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Patrick Loi
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $34,515
- **Award type:** 5
- **Project period:** 2021-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10362561

## Citation

> US National Institutes of Health, RePORTER application 10362561, Investigating the role of EZH2 as a therapeutic target in colorectal cancers (5F31CA260804-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10362561. Licensed CC0.

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