# Genetics and Biology of Metastatic Colorectal Cancer

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $364,755

## Abstract

Abstract/Summary
This proposal aims to dissect the actions of oncogenic KRAS (Kras*) its circuitry in controlling CRC immune
biology with the goal of illuminating effective therapeutic strategies for testing in CRC patients. An array of
molecular and pathobiological analyses comparing Kras* `on' versus Kras* `off' states in our mouse model of
human CRC has revealed that Kras* drives and maintains invasive and metastatic disease, with Kras*
expression correlating with a significant increase in myeloid derived suppressor cells (MDSCs) and decrease in
killer T-cells. Preliminary mechanistic studies have shown that Kras* activates TGFβ, which in turn represses
IRF2 (a master interferon regulatory factor), resulting in suppression of interferon response. The interferon
network normally functions to promote anti-tumor responses. Thus, our overall goal in this study is to evaluate
two hypotheses: (1) that Kras*/TGFβ-mediated repression of IRF2 creates an immune suppressive tumor
microenvironment enabling cancer progression, and (2) that Kras*-driven immune suppression may provide a
basis for the de novo resistance to immune checkpoint blockade (ICB) therapy observed in the majority of CRC
patients. To achieve these goals, we propose the following Specific Aims: In Aim 1, we will characterize the
immune suppressive cell subtypes driven by Kras* in primary CRC utilizing our novel CRC mouse model, and
evaluate the effects of Kras* mutation on MDSC and TAM activities to identify the signaling molecules
governing immune suppression in these tumors. In Aim 2, we will determine the mechanism by which TGFβ
suppresses IRF2, and identify the immune circuits regulated by IRF2 in Kras*-driven CRC that may contribute
to an immune suppressive tumor microenvironment enabling cancer progression. In Aim 3, we will investigate
whether the neutralization of key Kras*-regulated targets in CRC can reverse primary resistance to immune
checkpoint blockade therapy. Collectively, this proposal aims to identify novel combinations to improve the
ICB sensitivity in Kras* CRC.

## Key facts

- **NIH application ID:** 10229510
- **Project number:** 5R01CA231360-04
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** RONALD ANTHONY DEPINHO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $364,755
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10229510

## Citation

> US National Institutes of Health, RePORTER application 10229510, Genetics and Biology of Metastatic Colorectal Cancer (5R01CA231360-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10229510. Licensed CC0.

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