# Project 1 - Integrating targeted and immune therapies for BRAF mutant colorectal cancer

> **NIH NIH P50** · DANA-FARBER CANCER INST · 2022 · $356,409

## Abstract

Project Summary 
BRAF inhibitors lack efficacy in BRAF mutant (BRAFm) CRC (response rate only 5%) in contrast to 
response rates of >50% in BRAFm melanoma. Key studies conducted as part of our prior SPORE project 
identified feedback networks present in CRC (but absent in melanoma) that lead to rapid reactivation of 
MAPK signaling following BRAF inhibition, as primary drivers of resistance. This critical discovery led to 
clinical trials of BRAFi-based therapeutic combinations designed to block MAPK reactivation, resulting in 
an increased response rate for BRAFm CRC patients from 5% to >30%. Despite these therapeutic 
advances, clinical benefit is not durable, with a median PFS of only 4-5 months. Here we will explore 
potential cooperativity between targeted MAPK inhibition (MAPKi) and immune checkpoint blockade 
(ICB) to convert less immune responsive tumors to more immunogenic tumors. BRAFm CRC represents 
a prime population for exploring potential cooperativity, as 20-30% of metastatic BRAFm CRCs harbor 
MSI, which confers responsiveness to ICB. Moreover, we have observed durable responses of >5 years 
in MSI BRAFm CRC patients receiving MAPKi alone. In MSS BRAFm CRC patients, we see marked 
induction of CD4+ and CD8+ T-cells with MAPKi alone in paired tumor biopsies, and our preclinical 
mouse models demonstrate a cooperative effect of MAPKi and PD-1 IC in MSS BRAFm CRC. We 
propose a comprehensive effort using innovative immune competent BRAFm CRC mouse models, 
cutting-edge molecular and immune analyses of paired pre- and on-treatment tumor biopsies, and novel 
clinical trials to explore combined MAPKi and ICB as a strategy to achieve durable benefit in BRAFm 
CRC patients. Aim 1 will define the effects of MAPKi alone and with PD-1 ICB on immunogenicity of 
BRAFm CRC and anti-tumor immunity using immunologic and transcriptional profiling approaches to 
analyze novel BRAFm CRC models and a unique collection of paired pre-treatment and on-treatment 
biopsies from BRAFm CRC patients given BRAF/EGFR/MEKi. Aim 2 will conduct clinical trials and 
correlative studies of novel immune and targeted combinations for BRAFm CRC, evaluating clinical 
efficacy of combined BRAF/MEK/PD-1 inhibition. We will collaborate with the Pathology Core for 
multiplexed immune analysis of tumor biopsies, and the Biostats Core for analysis of bulk and single cell 
RNAseq and whole-exome sequencing. These studies will provide key insights to guide design of future 
trials. Aim 3 will define mechanisms of response and resistance to combined MAPKi and ICB in BRAFm 
CRC mouse models, and test strategies to overcome resistance to MAPKi/anti-PD-1 using combined ICB 
and modulators of immunosuppressive mechanisms defined by our analyses in Aims 1 and 2. These 
studies will define the potential synergy between MAPKi and ICB in BRAFm CRC and mechanisms of 
response and resistance to establish a new therapeutic paradigm for this lethal CRC subtype

## Key facts

- **NIH application ID:** 10456158
- **Project number:** 5P50CA127003-14
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Ryan Bruce Corcoran
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $356,409
- **Award type:** 5
- **Project period:** 2007-04-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10456158

## Citation

> US National Institutes of Health, RePORTER application 10456158, Project 1 - Integrating targeted and immune therapies for BRAF mutant colorectal cancer (5P50CA127003-14). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10456158. Licensed CC0.

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