# Project 3: MRI Imaging of Redox Active Fe Predicts GBM Responses to Pharmacological Ascorbate

> **NIH NIH P01** · UNIVERSITY OF IOWA · 2021 · $372,858

## Abstract

Project Summary/Abstract - Project 3:
Glioblastoma multiforme (GBM) is the most common malignant brain tumor in the United States but despite the
aggressive treatment GBM has a dismal prognosis with a median overall survival of ~15 months. Investigators
in Project 3 have found that pharmacological ascorbate (P-AscH-), is a promising adjuvant to chemo-radiation
therapy in GBM exploiting fundamental differences in oxidative metabolism. Preliminary data demonstrate the
selective toxicity of P-AscH- to GBM cells, relative to normal human astrocytes (NHA), occurs via H2O2-induced
oxidative stress mediated by redox active Fe ions. Furthermore, in a pre-clinical GBM model as well as in a
phase 1 clinical trial (NCT01752491), they found that P-AscH- (achieving ~20 mM [plasma]) + radiation and
temozolomide therapy was well-tolerated with minimal adverse events while showing encouraging therapeutic
responses. Finally, preliminary data also support the idea that magnetic resonance (MR) imaging may be
capable of detecting the redox state of Fe (i.e., Fe+2/Fe+3) for predicting responses to P-AscH- in combination
with chemo-radiation therapy via assessing changes of T2* relaxometry.
 Currently, there is no clear understanding of mechanisms causing the differential susceptibility of GBM vs.
normal brain cells to P-AscH- in vivo. Project 3 will test the hypothesis that P-AscH- selectively increases
labile redox active Fe associated H2O2 formation in human GBM cells, relative to normal astrocytes,
leading to increased oxidative DNA damage and increased sensitivity of GBM cells to radiation and
temozolomide that can be assessed in vivo using MR imaging with T2* relaxometry and quantitative
susceptibility mapping. Aim 1 will determine if P-AscH--induced increases in intracellular [H2O2] mediate
chemo-radiosensitization in patient derived GBM cells of Proneural, Neural, Classical and Meschymal
subtypes relative to normal human astrocytes (NHA) via enhanced DNA double strand breaks and differences
in H2O2 metabolism in GBM cells. Aim 2 will determine if increased labile iron pools (LIP) mediate the
sensitivity of GBM vs. NHA to P-AscH--induced chemo-radiosensitization. Aim 3 will determine in orthotopic
GBM xenograft models if P-AscH- induced regulation of the redox-active LIP and selective sensitization to
radiation and chemotherapy can be predicted using T2* MRI imaging and quantitative susceptibility mapping
as well as standard biochemical assays. Completion of the aims will define biochemical mechanisms
underlying P-AscH--mediated selective chemo-radiosensitization of GBM cells in vitro and in vivo orthotopic
models as well as investigating highly innovative MR imaging approaches to predict responses. Project 3 is
also well-integrated into the overall theme of the PO1 to provide a new paradigm for exploiting fundamental
differences in redox metabolism to improve treatment efficacy in cancer patients using P-AscH-.

## Key facts

- **NIH application ID:** 10240532
- **Project number:** 5P01CA217797-04
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Bryan Allen
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $372,858
- **Award type:** 5
- **Project period:** 2018-09-19 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240532

## Citation

> US National Institutes of Health, RePORTER application 10240532, Project 3: MRI Imaging of Redox Active Fe Predicts GBM Responses to Pharmacological Ascorbate (5P01CA217797-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10240532. Licensed CC0.

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