# Drivers of metabolic plasticity promote radiation resistance in glioblastoma multiforme

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $349,713

## Abstract

ABSTRACT
Radiation therapy (RT) is a very effective treatment modality for improving local control
and overall survival for many cancer types. However, glioblastoma multiforme (GBM)
displays remarkable radioresistance. Although, post-surgical RT (total dose of 60Gy in
2Gy fractions) is the only treatment modality that increases overall survival for GBM
patients, GBM universally recurs and is fatal. Resistance to RT is therefore a major
contributor to treatment failure. Overcoming radiation resistance of these tumors is one
of the major remaining frontiers in Radiation Oncology that, if resolved, could
dramatically improve outcomes in this disease. Amongst the many contributing factors
that have been proposed, GBM metabolism and its role in generating resistance to
oxidative stress, such as during RT is a promising therapeutic angle that we will exploit
in this proposal. Specifically, we have evidence that irradiated GBM cells reprogram their
metabolism towards antioxidant pathways, by funneling glucose through the NADPH-
generating pentose phosphate pathway (PPP). Such metabolic reprogramming during
RT is mediated in part by the glycolytic enzyme PKM2 and in part by the transcription
factor NRF2. Oxidative stress-dependent inactivation of PKM2 or activation of NRF2,
both result in rerouting of glycolytic intermediates into the PPP. In addition, we have
evidence that PKM2 is a NRF2 target. Therefore, we hypothesize that PKM2 and NRF2
cooperate in driving an antioxidant metabolic response in irradiated GBM cells that
promotes resistance to RT. Of importance is the fact that PKM2 is overexpressed in
GBM tumors, while normal brain tissue only expresses PKM1. Also, small molecule
activators of PKM2 are available that exacerbate oxidative stress and have anti-tumor
activity, although they have not been tested in GBM or with RT. These activators cross
the blood brain barrier making them suitable for combining with RT to sensitize GBM
tumors. Therefore, it is also proposed that interfering with the NRF2-PKM2-metabolism
axis would limit the antioxidant, pro-survival metabolic reprogramming induced by
radiation and improve the effect of RT in human and mouse models of GBM.

## Key facts

- **NIH application ID:** 10645199
- **Project number:** 5R01CA251872-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Erina Vlashi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $349,713
- **Award type:** 5
- **Project period:** 2020-07-06 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10645199

## Citation

> US National Institutes of Health, RePORTER application 10645199, Drivers of metabolic plasticity promote radiation resistance in glioblastoma multiforme (5R01CA251872-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10645199. Licensed CC0.

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