# Drivers of Metabolic Plasticity Promote Radiation Resistance in Glioblastoma Multiforme

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $330,894

## Abstract

Project Summary
Glioblastoma multiforme (GBM) is one of the most therapy-resistant tumors, with a dismal 5-year survival
rate of <10%. Intrinsic and acquired resistance to radiation therapy contributes significantly to the refractory
nature of these tumors. Ionizing radiation (IR) exerts its cytotoxic effects primarily by generating free
radicals, in particular reactive oxygen species (ROS). Moderating redox is therefore critical to mitigating
the lethal effects of IR and increase the effectiveness of RT. In this proposal we postulate that GBM tumors
can generate an antioxidant response to RT by rewiring their metabolism and this is a major mechanism
leading to their survival and treatment failure. As yet, little is known about the metabolic response of GBM
undergoing RT and the molecular drivers of metabolic plasticity are unknown. In the parent award we
provide evidence for radiation-induced metabolic reprogramming in GBM, which includes enhanced
consumption of glucose and glutamine by irradiated GBM cells and diversion of the flow of glycolytic
intermediates into the antioxidant, NADPH-producing pentose phosphate pathway (PPP). Based on
preliminary studies, we hypothesize that the IR-induced metabolic reprogramming in GBM is orchestrated
in part by the activation of the transcription factor NRF2, which turns on the transcription of metabolic
enzymes that drive the PPP. We also hypothesize that diversion of glycolytic intermediates into the PPP is
further amplified by the IR-induced inhibition of the redox-sensitive, glycolytic enzyme PKM2.
Here, we propose to expand our current working model based on new compelling data that point to serine
synthesis pathway (SSP) as an additional radiation-induced metabolic pathway that also contributes to
metabolic rewiring in GBM. The radiation-enhanced SSP activity is driven by NRF2, in keeping with NRF2
being the orchestrator of IR-induced metabolic reprogramming in GBM. However, we have also shown
that IR activates the HIF-1 pathway independently of hypoxia and IR-induced upregulation of SSP enzyme
expression is completely prevented by HIF-1a inhibition, suggesting dual roles for these two redox-
sensitive factors in coordinating the metabolic rewiring of GBM following RT that drives antioxidant
pathways and IR resistance through the PPP and de novo SSP, with assistance from PKM2 blockade.
Together with the body of data from the parent award, these studies will build a comprehensive picture of
radiation-induced metabolic rewiring in GBM that will illuminate interventional strategies aimed at
improving RT outcomes in this dreadful disease.

## Key facts

- **NIH application ID:** 10437534
- **Project number:** 3R01CA251872-03S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Erina Vlashi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $330,894
- **Award type:** 3
- **Project period:** 2020-07-06 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10437534

## Citation

> US National Institutes of Health, RePORTER application 10437534, Drivers of Metabolic Plasticity Promote Radiation Resistance in Glioblastoma Multiforme (3R01CA251872-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10437534. Licensed CC0.

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