# Molecular Strategies to Widen the Therapeutic Index of Radiotherapy

> **NIH NIH P01** · STANFORD UNIVERSITY · 2022 · $2,146,256

## Abstract

Abstract (Overall)
The central hypothesis of this program project grant is that our knowledge of tumor genomics and the
microenvironment, combined with our understanding of normal tissue biology, can be exploited to protect normal
tissues from radiation (RT) damage while selectively killing tumor cells, leading to an improved therapeutic index.
The projects and cores that comprise this grant represent a highly integrated effort with a single focus of
widening the therapeutic index of radiotherapy. Project 1 (Giaccia) will modulate the radiosensitivity of
tumors and radioprotection of normal tissues via the complement pathway and will aim to understand the
mechanistic basis of how inhibition of C5aR1 serves to sensitize gastrointestinal (GI) tumors and protect
abdominal tissues from RT. They will also explore the role of C5aR1 inhibition in other normal tissues in
collaboration with the other projects and cores. Project 2 (Le) will focus on activating Aldehyde Dehydrogenase-
3A1 (ALDH3A1) to mitigate RT-induced severe dry mouth in head and neck cancer (HNC) patients by testing d-
limonene, a novel ALDH3A1 activator identified by their group, in a phase I clinical trial. While focusing on HNC,
they will evaluate the effect of d-limonene in radioprotecting other normal tissues in collaboration with the other
projects and cores. Project 3 (Diehn) will develop a personalized radiosensitization strategy for patients with
KEAP1/NFE2L2 mutant non-small cell lung cancer (NSCLC) based on their prior work that identified mutations
in this pathway as key determinants of radioresistance in NSCLC patients. They will test the hypothesis that
glutaminase inhibition preferentially radiosensitizes KEAP1 mutant NSCLC without enhancing normal lung tissue
toxicity. While concentrating on NSCLC, they will also evaluate the effects of glutaminase inhibition in other
KEAP1/NFE2L2 mutant tumors and its effect on normal tissues in collaboration with other projects and cores.
Project 4 (Rankin) tests the hypothesis that inhibition of FTO (Fat mass and obesity-associated protein), an RNA
demethylases, would enhance the efficacy of RT in multiple solid tumors. This is based on their preliminary data
showing that FTO is overexpressed in many cancers including cervical, lung and HN cancers, that FTO inhibition
reduces cancer cell growth and enhances RT sensitivity through the inhibition of glutamine metabolism. They
will determine the therapeutic effects and mechanism of action of FTO inhibition in combination with RT in
multiple cancer models in collaboration with the other projects and cores. They will also study the effect of FTO
inhibition on normal tissue response to RT. If successful, D-limonene, a nutraceutical, can be rapidly tested in
larger phase II and III clinical trials for future clinical use. Similarly, PMX 205 (a C5aR1 inhibitor) and CB-839 (a
glutaminase inhibitor) are currently being evaluated in clinical trials for other clinical indications while drugs
targ...

## Key facts

- **NIH application ID:** 10334198
- **Project number:** 1P01CA257907-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Maximilian Diehn
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,146,256
- **Award type:** 1
- **Project period:** 2022-09-21 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10334198

## Citation

> US National Institutes of Health, RePORTER application 10334198, Molecular Strategies to Widen the Therapeutic Index of Radiotherapy (1P01CA257907-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10334198. Licensed CC0.

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