# Targeting metabolic vulnerabilities in glioblastoma

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $490,971

## Abstract

Glioblastoma (GBM) is one of the most lethal of all cancers. As such, new therapeutic strategies are desperately
needed. We and others have shown that metabolic reprogramming is a key feature of GBM to accommodate the
heightened energetic, nutrient and redox requirements to support tumor growth and survival. The most prominent
characteristics of this metabolic reprogramming are a shift to high glucose metabolism. Recent evidence
suggests that oncogenic signaling regulates glucose utilization in GBM. Accordingly, inhibition of oncogenic
signaling can disrupt glucose metabolism, leading to reduced metabolic intermediates for cellular energetic and
anabolic processes. However, the therapeutic potential of targeting oncogene-regulated glucose metabolism in
GBM remains enigmatic. We present compelling preliminary data demonstrating that acute inhibition of EGFR –
the most frequently altered oncogene in GBM - can rapidly and potently attenuate glucose uptake and
consequently glucose metabolism in patient-derived GBM models. As a result of this “altered” metabolic state,
GBM models show synergistic intrinsic apoptosis to pharmacological p53 activation. We also demonstrate that
18F-flurodeoxyglucose (FDG) and positron emission tomography (PET) can be used as a rapid (within hours),
non-invasive biomarker that may predict sensitivity to this new rational combination. In this revised R01
application, we extend on these exciting preliminary studies and investigate in Aim 1 the precise signaling and
metabolic mechanisms whereby EGFR inhibition sensitizes GBMs to p53 activation. In Aim 2, using established
BH3 profiling technology, we propose to characterize the pro- and anti-apoptotic signatures resulting in p53-
dependent lethality following inhibition of EGFR-regulated glucose metabolism. Finally, in Aim 3 we will
determine whether combined targeting of oncogene-regulated glucose metabolism (e.g., with EGFRi) and
pharmacological p53 activation (in collaboration with Roche) is efficacious in direct-from-patient orthotopic GBM
xenografts. We will also evaluate whether 18FDG PET can serve as a robust non-invasive biomarker for
quantifying rapid changes in glucose metabolism with EGFRi via a pilot clinical trial in molecularly enriched
recurrent GBM patients. The studies proposed in this application present a new combination strategy, coupled
with a non-invasive predictive biomarker, aimed for specific manipulation of metabolism and apoptotic pathways
in malignant glioma and have the long term potential to shift current approaches in glioma therapy.

## Key facts

- **NIH application ID:** 9985754
- **Project number:** 5R01CA213133-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** David A. Nathanson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $490,971
- **Award type:** 5
- **Project period:** 2017-08-07 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985754

## Citation

> US National Institutes of Health, RePORTER application 9985754, Targeting metabolic vulnerabilities in glioblastoma (5R01CA213133-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9985754. Licensed CC0.

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