# Understanding methionine metabolism and its therapeutic potential in cancer

> **NIH NIH R00** · BAYLOR COLLEGE OF MEDICINE · 2022 · $249,000

## Abstract

Cancers have different nutritional requirements from their healthy counterparts. Herein,
targeting the enzymes and thus the metabolic networks that constitute these different metabolic
requirements is attracting numerous drug development efforts. While targeting enzymes in
cancer-specific metabolic pathways has been successful, whether metabolism can be affected
to similar extents by nutritional manipulation in specific and controlled manners is largely
unknown. Methionine availability affects one-carbon cycle flux, DNA and histone methylation
and thus epigenetic programming. Dietary methionine restriction (MR) also promotes metabolic
health and extends insect and mammalian lifespan, two anti-cancer features. Thus, we
hypothesize that dietary MR could inhibit tumor growth and enhance anti-cancer therapy. Our
preliminary data show that dietary MR, a cost-effective approach, alters plasma methionine
effectively in both healthy mice and humans. MR mediates promising tumor outcomes: in two
RAS-driven colorectal cancer (CRC) patient-derived xenografts (PDX) models, it delays tumor
growth and sensitizes tumor to 5-Fluorouracil, a frontline chemotherapy for CRC; and in an
autochthonous KRASG12D+/-;TP53-/- soft tissue sarcoma model, it reaches a striking
synergistic effect with radiation. In these models, cysteine and methionine metabolism is the
most impacted metabolic pathway in the tumor and the plasma. However, the molecular
mechanisms by which dietary MR interacts with metabolism and eventually mediates tumor
outcome are unknown. To explore the mechanisms, I propose to focus on CRC PDX models
through the following two aims. In Aim 1, I will first employ a state of the art metabolomics
approach established in our laboratory to evaluate the metabolic alterations in tumor and non-
tumor tissues by dietary MR or a combination of MR and 5-FU. Upon consolidation of the
findings in vitro, I will conduct dietary interventions by supplementing cysteine or betaine to
determine the contribution of methionine as a sulfur donor and a one-carbon donor to tumor
growth in CRC PDX models, respectively. In Aim 2, I will first characterize the epigenetic and
genetic adaptions to dietary MR in tumor and CRC cell linesusing bisulfite sequencing, ATAC-
seq, ChIP-seq, and RNA-seq. With these data, I will construct a metabolic network and perform
a functional screen of metabolic pathway genes using CRISPR/Cas9 technology. The outcome
will reveal the metabolic, genetic, and epigenetic mechanisms underlying dietary MR-mediated
tumor inhibition alone and in adjuvant with 5-FU in CRC. It is also anticipated to provide target
metabolite and genes for future hypothesis generation and novel therapy targeting cancer
metabolism.

## Key facts

- **NIH application ID:** 10554637
- **Project number:** 4R00CA237618-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Xia Gao
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2022-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10554637

## Citation

> US National Institutes of Health, RePORTER application 10554637, Understanding methionine metabolism and its therapeutic potential in cancer (4R00CA237618-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10554637. Licensed CC0.

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