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Redox manipulation of iron to improve glioblastoma therapy: A phase 1 trial

Award Number: R21CA270742
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/16/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Redox manipulation of iron to improve glioblastoma therapy: A phase 1 trial - Project Summary & Abstract Glioblastoma (GBM) is a deadly primary brain cancer with a median overall survival (OS) of only 14-16 months. Despite a treatment regimen including surgical resection followed by radio-chemo-therapy, the majority of patients will recur within 7 months of diagnosis. We identified in a phase 1 trial that pharmacological ascorbate (PAscH-; IV vitamin C reaching ≈ 20 mM in plasma) combined with standard GBM therapy is well tolerated with promising outcomes in poor prognosis subjects with MGMT positive/IDH1 wild type tumors. This led to the recent completion of enrollment of a PAscH- GBM phase 2 trial (NCT02344355) treated with standard radiation and temozolamide and PAscH-. Median OS in the GBM phase 2 trial was 22 months. Our research team made the exciting mechanistic observation that PAscH- selectively enhances GBM radio- chemo-therapy, relative to normal human astrocytes, because of differences in the metabolism of redox active iron (Fe). This mechanism results from the selective increased Fe-mediated oxidation of ascorbate in tumor tissue leading to the formation of hydrogen peroxide (H2O2). H2O2 can be directly toxic to cancer cells or can react with Fe through Fenton chemistry to produce hydroxyl radicals that damage DNA, proteins, and lipids and hence synergizes with radio-chemo-therapy. Furthermore, preliminary analysis of the PAscH- GBM phase 2 trial identified that subjects with increased tumor Fe, detected by magnetic resonance imaging (MRI) T2* relaxation, had significantly increased progression free survival (11.2 months vs. 5.7 months). This suggests T2* relaxation may be a non-invasive biomarker to predict Fe dependent response to PAscH-. Ferumoxotyol (FMX) is an Fe oxide nanoparticle used in glioma MR imaging. Preliminary pre-clinical data show that ascorbate and ionizing radiation facilitate the release of Fe from FMX that can be detected by alterations in MRI parameters (T1 enhancement and decreased T2* relaxation time). The released Fe would then be available for the therapeutic enhancement of PAscH-. In GBM human tumors, FMX mediated T1 enhancement detects Fe release for up to 72 hours after infusion in the tumor and surrounding edema volume. Given this exciting preliminary data, FMX may represent the ideal GBM imaging and therapy agent when combined with PAscH-. We hypothesize iron supplementation with FMX in combination with PAscH- and standard of care therapy will be safe and increase redox active Fe content (detected by T2* relaxation) in GBM tumors as part of a phase 1 clinical trial. Each subject’s GBM tumor will be analyzed by T2* MRI for changes in redox active Fe as well as assessing plasma for evidence of Fe overload and liver injury. Completion of these studies will assess the impact of the redox active Fe manipulation on GBM therapy. If successful, future phase 2 studies will investigate the potential of combining PAscH- and FMX with standard GBM therapy to improve survival and sensitize subjects that might not otherwise respond to PAscH- radio- chemo-therapy.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Treatment Research	000	2	4/29/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $172,653 )
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Treatment Research	000	2	3/14/2024	NON-COMPETING CONTINUATION	$163,567
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Treatment Research	001	2	4/17/2024	NON-COMPETING CONTINUATION	$9,086
														Subtotal = $172,653

Issue Date FY: 2023 ( Subtotal = $218,089 )
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Treatment Research	000	1	5/16/2023	NEW	$218,089
														Subtotal = $218,089

Grand Total All Awards = $390,742

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Redox manipulation of iron to improve glioblastoma therapy: A phase 1 trial

Award Number: R21CA270742

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/16/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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