# Dietary methionine restriction as a therapeutic strategy for metastatic melanoma

> **NIH NIH P20** · UNIVERSITY OF ARKANSAS AT FAYETTEVILLE · 2021 · $231,139

## Abstract

Project Summary – Project Leader Isabelle Racine Miousse 
 Nearly 10,000 Americans die from melanoma every year. Since 2011, immune checkpoint inhibitors have 
been approved for metastatic melanoma. These antibodies enhance a person’s immune system ability to 
recognize cancer cells. Despite a major improvement in remission rates, the majority of patients do not respond 
to immune checkpoint inhibitors. The identification of approaches to overcome immune checkpoint inhibitor 
resistance, as well as new therapeutic strategies to treat metastatic melanoma, are crucially needed. 
 Cancer cells rely on exogenous sources of methionine, contrarily to normal cells that can thrive off the 
remethylation of homocysteine. Our data shows that at levels that maintain body weight, a methionine restricted 
diet dramatically reduces tumor size and number of lung metastases in an immunocompetent murine melanoma 
model. Our preliminary data indicates that the effect involves mitochondrial function. Recent work highlighted 
the importance of mitochondrial function in immune checkpoint inhibitor responders versus nonresponders. The 
combination of methionine restriction and immune checkpoint inhibitor responsiveness has never been tested. 
In addition to direct effects on methionine dependent cancer cells, we have determined that alterations in dietary 
methionine affect the gut microbiome. It is now well-established that there are significant differences in the gut 
microbiomes of patients with metastatic melanoma that are associated with efficacy of immune checkpoint 
inhibitor therapy, and that responsiveness can be induced with fecal transplantation in animal models. However, 
the impact of a methionine-regulated microbiome on melanoma growth, metastasis, and immune checkpoint 
inhibitor responsiveness is unknown. 
 According to our data and supporting scientific literature, we hypothesize that dietary methionine restriction 
will promote antitumor mechanisms, including autophagy and microbiome alterations, which will increase 
immune checkpoint inhibitor responsiveness for metastatic melanoma. To test this hypothesis, we propose to 
study the effect of a methionine restricted diet in a preclinical, immunocompetent mouse model of melanoma. 
Following establishment of tumor, mice will receive a standard diet or an identical diet containing low levels of 
methionine to investigate the following: Aim 1) Determine whether methionine restriction increases 
responsiveness to immune checkpoint blockade in a preclinical mouse model. Aim 2) Determine the contribution 
of gut microbiota in methionine-dependent antitumor activity. 
 Our study investigates a novel approach to decrease mortality due to metastatic melanoma. We expect the 
results generated from our studies to be translatable to other types of malignancies, especially those for which 
immune checkpoint inhibitors are used for therapy.

## Key facts

- **NIH application ID:** 10090751
- **Project number:** 1P20GM139768-01
- **Recipient organization:** UNIVERSITY OF ARKANSAS AT FAYETTEVILLE
- **Principal Investigator:** Isabelle Racine Miousse
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $231,139
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10090751

## Citation

> US National Institutes of Health, RePORTER application 10090751, Dietary methionine restriction as a therapeutic strategy for metastatic melanoma (1P20GM139768-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10090751. Licensed CC0.

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