# Metabolic Reprogramming in Brain Tumors

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $644,538

## Abstract

ABSTRACT
The goal of this competitive renewal is to identify and validate novel translatable metabolic imaging biomarkers
of response to advanced clinically-relevant therapies that target isocitrate dehydrogenase 1 (IDH1) in the
treatment of mutant IDH1 glioma. The IDH1 mutation is a `driver mutation' that is present in 70-90% of low-
grade glioma and secondary upgraded glioblastoma. In an effort to improve the treatment of mutant IDH1
tumors, novel therapeutic approaches are been developed, and data shows that siRNA targeting both wild-type
(wt) and mutant IDH1, as well as new dual (wt/mutant) IDH inhibitors now in clinical trials, lead to a clear
response. However, no noninvasive imaging methods are available to assess drug-target engagement or
predict response. During the first funding period of this grant we identified several mutant IDH1-driven 1H
magnetic resonance spectroscopy (MRS)-detectable metabolic alterations, and developed novel translational
hyperpolarized 13C MRS-based imaging approaches that inform on the presence of the mutation. Our
preliminary data indicate that response to treatment with emerging dual inhibitors is associated with a reversal
of all the 1H MRS-detectable metabolic alterations observed in mutant cells but not with all of the associated
hyperpolarized 13C MRS-detectable metabolic fluxes, likely reflecting inhibition of wt IDH1. In addition, levels of
glutathione (GSH) and the ratio of GSH to its oxidized form GSSG drop, pointing to additional imageable
metabolic reactions associated with response. We therefore hypothesize that using some of our previously
identified MRS biomarkers of mutant IDH1, as well as imaging biomarkers of redox status, it will be possible to
monitor the therapeutic effects of dual IDH inhibitors that are entering the clinic.
Aim 1. To identify 1H and hyperpolarized 13C MRS-detectable metabolic biomarkers associated with
response to novel IDH-targeting therapies in mutant IDH1 cells. We will investigate genetically-engineered
and patient-derived cell models, and use 1H and hyperpolarized 13C MRS to identify the imageable metabolic
alterations that are uniquely associated with response to therapy as determined by inhibition in cell proliferation
and/or clonogenic potential.
Aim 2. To mechanistically validate 1H and hyperpolarized 13C MRS imaging biomarkers of response. We
will use a range of biochemical, cell, and molecular biological assays as well as specific inhibitors to determine
the mechanistic link between drug action and the metabolic imaging biomarkers identified in Aim 1.
Aim 3. To confirm in vivo the 1H and hyperpolarized 13C MRS metabolic imaging biomarkers as
indicators of tumor response to novel IDH-targeting therapies in mutant IDH1 tumors. We will treat
tumor-bearing mice, and use MRI with 1H and hyperpolarized 13C MRSI, to longitudinally monitor the effect of
therapy on tumor growth and metabolism, and assess the value of our metabolic imaging biomarkers for
prediction of r...

## Key facts

- **NIH application ID:** 9868811
- **Project number:** 5R01CA172845-08
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Sabrina Miriam Ronen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $644,538
- **Award type:** 5
- **Project period:** 2013-02-05 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868811

## Citation

> US National Institutes of Health, RePORTER application 9868811, Metabolic Reprogramming in Brain Tumors (5R01CA172845-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9868811. Licensed CC0.

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