# Optimizing radiation therapy through the manipulation of glutamine metabolism

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $374,063

## Abstract

PROJECT SUMMARY
Up to 50% of patients with locally advanced cervical cancer treated with the current standard of
care will fail this treatment, and there is currently no cure for recurrent or metastatic disease. As
a result of our recently completed studies of the connection between cervical cancer metabolism
and radiation resistance, we have found that cervical cancer is highly dependent upon glutamine.
Recent data has also demonstrated that targeting glutamine metabolism not only limits tumor cell
growth, but also improves anti-tumor immunity by reprogramming macrophages in the tumor
microenvironment (TME) towards a more pro-inflammatory phenotype. Given that radiation
therapy (RT) has also been shown to promote anti-tumor immunity, these findings suggest that
the combination of targeting glutamine metabolism and RT may synergize to enhance anti-tumor
immunity and achieve long term tumor control. The purpose of this renewal R01 application is to
perform preclinical mechanistic studies and a corresponding investigator-initiated clinical trial to
support targeting glutamine metabolism with radiation therapy as a novel therapeutic strategy for
radiation-resistant cervical cancers. Our working hypothesis is that inhibition of glutamine
metabolism enhances radiation sensitivity through synergistic metabolic effects on tumor cells
and immune cells within the TME. In Specific Aim 1, we will test whether the combination of the
glutaminase inhibitor, CB-839, and chemoradiation improves anti-tumor immune responses using
paired human tumor specimens collected in the context of an investigator initiated Phase I/II
clinical trial. In Specific Aim 2, using 2D and 3D co-culture systems, we will determine whether
the cytotoxic effects of inhibition of glutamine metabolism are mediated primarily through
metabolic effects on tumor cells versus the combined effects on tumor cells and macrophages. In
Specific Aim 3, using a patient derived xenograft (PDX) library and a novel genetically
engineered mouse model (GEMM), we will determine whether the radiation modifying properties
of CB-839 are dependent upon metabolic editing of the tumor microenvironment, and test new
therapy combinations that will support future clinical trials. This work will generate a mechanistic
rationale and test predictive biomarkers for the inhibition of glutamine metabolism and RT, and in
so doing complete the first-in-human trial of CB-839 + chemoradiation in cervical cancer. This
clinical trial is unique in that it includes an investigational new drug, CB-839, administered with
both conventionally fractionated external beam RT as well as high dose rate hypofractionated
brachytherapy. This design will provide valuable data in humans regarding the effects of RT dose
and fractionation on chemoradiation and CB-839 associated changes in the TME.

## Key facts

- **NIH application ID:** 10441995
- **Project number:** 2R01CA181745-06A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Julie Kristina Schwarz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $374,063
- **Award type:** 2
- **Project period:** 2014-09-16 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10441995

## Citation

> US National Institutes of Health, RePORTER application 10441995, Optimizing radiation therapy through the manipulation of glutamine metabolism (2R01CA181745-06A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10441995. Licensed CC0.

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