# Project 4: FTO Inhibition to Enhance the Therapeutic Index of Radiotherapy

> **NIH NIH P01** · STANFORD UNIVERSITY · 2022 · $362,265

## Abstract

Abstract (Project 4)
Radiation therapy is a standard treatment for many solid tumors including cervical, non-small cell lung (NSCLC)
cancer, and head and neck cancer. While effective in a large proportion of patients, local failure remains a
significant cause of patient morbidity and mortality. An attractive strategy to radiosensitize tumors is targeting
cancer-specific glutamine metabolic reprogramming as this pathway supports tumor growth, survival, oxidative
stress responses and DNA damage repair. The RNA demethylase FTO is emerging as a therapeutic target for
cancer therapy as it is overexpressed and oncogenic in several cancers including cervical, non-small cell lung
cancer (NSCLC), and head and neck cancers. However, FTO has not previously been explored as a target for
tumor radiosensitization. Preliminary studies demonstrate that FTO inhibition reduces tumor growth and survival
in vitro and in vivo. At the molecular level, FTO inhibition reduces SLC1A5 expression and glutamine uptake in
cancer cells. Importantly, FTO inhibition radiosensitizes cervical and KEAP1 mutant NSCLC cancer cells. This
proposal will test the hypothesis that inhibition the RNA demethylase fat-mass and obesity-associated
(FTO) will enhance the therapeutic index of radiotherapy in solid tumors through the inhibition of
glutamine metabolism. Aim 1 will determine the anti-tumor effects of FTO inhibition in combination with
radiation on a range of solid tumors cancers using genetic and pharmacologic approaches. Aim 2 determine if
FTO inhibition enhances the radiation response in cancer cells by reducing glutamine metabolism, oxidative
stress and/or DNA damage repair responses using knockdown and gain of function approaches. Aim 3 will test
the hypothesis that FTO inhibition will not impact the radiation sensitivity of normal tissues that develop radiation-
induced toxicity when treating cervical, NSCLC and HNSCC tumors. The acute and late effects of FTO inhibition
on the radiation response in the bone marrow, intestine (collaboration with Project 1), salivary gland and oral
mucosa (collaboration with Project 2), and lung (collaboration with Project 3) will be analyzed using models of
global conditional FTO inactivation in adult mice. Together with Projects 1, 2 and 3 this project will investigate
the role of FTO in both the tumor and normal tissue radiation response with the goal of ascertaining the
therapeutic potential of FTO-based radiosensitizers. In addition to determining the tumor types that can be
effectively and safely treated with FTO inhibition, they will use cutting edge analytical tools to study the
mechanism of action. Successful completion of these aims will 1) identify FTO is an epitranscriptomic regulator
of cancer cell glutamine metabolism and oxidative stress; 2) provide the preclinical data to support FTO as a
safe and effective molecular target to radiosensitize tumors; 3) provide proof of concept studies to demonstrate
that small molecule targeting ...

## Key facts

- **NIH application ID:** 10334202
- **Project number:** 1P01CA257907-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Erinn B Rankin
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $362,265
- **Award type:** 1
- **Project period:** 2022-09-21 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10334202

## Citation

> US National Institutes of Health, RePORTER application 10334202, Project 4: FTO Inhibition to Enhance the Therapeutic Index of Radiotherapy (1P01CA257907-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10334202. Licensed CC0.

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