Magnetic resonance imaging (MRI) of pharmacological ascorbate-induced iron redox state as a biomarker in subjects undergoing radio-chemotherapy

Cameron M Cushing; Michael S Petronek; Kellie L Bodeker; Sandy Vollstedt; Heather A Brown; Emyleigh Opat; Nancy J Hollenbeck; Thomas Shanks; Daniel J Berg; Brian J Smith; Mark C Smith; Varun Monga; Muhammad Furqan; Matthew A Howard; Jeremy D Greenlee; Kranti A Mapuskar; Joel St-Aubin; Ryan T Flynn; Joseph J Cullen; Garry R Buettner; Douglas R Spitz; John M Buatti; Bryan G Allen; Vincent A Magnotta

doi:10.1016/j.redox.2020.101804

Back

Magnetic resonance imaging (MRI) of pharmacological ascorbate-induced iron redox state as a biomarker in subjects undergoing radio-chemotherapy

Journal article

Open access

Peer reviewed

Magnetic resonance imaging (MRI) of pharmacological ascorbate-induced iron redox state as a biomarker in subjects undergoing radio-chemotherapy

Cameron M Cushing, Michael S Petronek, Kellie L Bodeker, Sandy Vollstedt, Heather A Brown, Emyleigh Opat, Nancy J Hollenbeck, Thomas Shanks, Daniel J Berg, Brian J Smith, …

Redox biology, Vol.38, pp.101804-101804

01/2021

DOI: 10.1016/j.redox.2020.101804

PMID: 33260088

Files and links (1)

url

https://doi.org/10.1016/j.redox.2020.101804View

Published (Version of record) Open Access

Abstract

Pharmacological ascorbate (P-AscH-) combined with standard of care (SOC) radiation and temozolomide is being evaluated in a phase 2 clinical trial (NCT02344355) in the treatment of glioblastoma (GBM). Previously published data demonstrated that paramagnetic iron (Fe3+) catalyzes ascorbate's oxidation to form diamagnetic iron (Fe2+). Because paramagnetic Fe3+ may influence relaxation times observed in MR imaging, quantitative MR imaging of P-AscH--induced changes in redox-active Fe was assessed as a biomarker for therapy response. Gel phantoms containing either Fe3+ or Fe2+ were imaged with T2* and quantitative susceptibility mapping (QSM). Fifteen subjects receiving P-AscH- plus SOC underwent T2* and QSM imaging four weeks into treatment. Subjects were scanned: pre-P-AscH- infusion, post-P-AscH- infusion, and post-radiation (3–4 h between scans). Changes in T2* and QSM relaxation times in tumor and normal tissue were calculated and compared to changes in Fe3+ and Fe2+ gel phantoms. A GBM mouse model was used to study the relationship between the imaging findings and the labile iron pool. Phantoms containing Fe3+ demonstrated detectable changes in T2* and QSM relaxation times relative to Fe2+ phantoms. Compared to pre-P-AscH-, GBM T2* and QSM imaging were significantly changed post-P-AscH- infusion consistent with conversion of Fe3+ to Fe2+. No significant changes in T2* or QSM were observed in normal brain tissue. There was moderate concordance between T2* and QSM changes in both progression free survival and overall survival. The GBM mouse model showed similar results with P-AscH- inducing greater changes in tumor labile iron pools compared to the normal tissue. T2* and QSM MR-imaging responses are consistent with P-AscH- reducing Fe3+ to Fe2+, selectively in GBM tumor volumes and represent a potential biomarker of response. This study is the first application using MR imaging in humans to measure P-AscH--induced changes in redox-active iron. •Quantitative imaging can detect tissue differences in Fe3+ and Fe2+ concentrations.•Pharmacological ascorbate treatment increases T2* relaxation times in GBM tumors.•T2* is a potential biomarker of response in GBM subjects to treatment with pharmacological ascorbate.

Quantitative imaging

QSM

GBM

Pharmacological ascorbate

Details

Title: Subtitle: Magnetic resonance imaging (MRI) of pharmacological ascorbate-induced iron redox state as a biomarker in subjects undergoing radio-chemotherapy
Creators: Cameron M Cushing - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, USA
Michael S Petronek - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, USA
Kellie L Bodeker - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, USA
Sandy Vollstedt - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, USA
Heather A Brown - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, USA
Emyleigh Opat - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, USA
Nancy J Hollenbeck - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, USA
Thomas Shanks - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, USA
Daniel J Berg - Division of Hematology and Oncology, Department of Internal Medicine, Holden Comprehensive Cancer Center, University of Iowa Hospitals & Clinics, Iowa City, IA, USA
Brian J Smith - Department of Biostatistics, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, USA
Mark C Smith - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, USA
Varun Monga - Division of Hematology and Oncology, Department of Internal Medicine, Holden Comprehensive Cancer Center, University of Iowa Hospitals & Clinics, Iowa City, IA, USA
Muhammad Furqan - Division of Hematology and Oncology, Department of Internal Medicine, Holden Comprehensive Cancer Center, University of Iowa Hospitals & Clinics, Iowa City, IA, USA
Matthew A Howard - Department of Neurosurgery, University of Iowa Hospitals & Clinics, Iowa City, IA, USA
Jeremy D Greenlee - Department of Neurosurgery, University of Iowa Hospitals & Clinics, Iowa City, IA, USA
Kranti A Mapuskar - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, USA
Joel St-Aubin - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, USA
Ryan T Flynn - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, USA
Joseph J Cullen - Department of Surgery, University of Iowa College of Medicine, Iowa City, IA, USA
Garry R Buettner - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, USA
Douglas R Spitz - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, USA
John M Buatti - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, USA
Bryan G Allen - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, USA
Vincent A Magnotta - Department of Radiology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, USA
Resource Type: Journal article
Publication Details: Redox biology, Vol.38, pp.101804-101804
DOI: 10.1016/j.redox.2020.101804
PMID: 33260088
NLM abbreviation: Redox Biol
ISSN: 2213-2317
eISSN: 2213-2317
Publisher: Elsevier B.V
Grant note: DOI: 10.13039/100001634, name: Gateway for Cancer Research; DOI: 10.13039/100000002, name: National Institutes of Health
Language: English
Date published: 01/2021
Academic Unit: Neurology; Psychiatry; Pathology; Biostatistics; Surgery; Otolaryngology; Roy J. Carver Department of Biomedical Engineering; Radiology; Iowa Neuroscience Institute; Radiation Oncology; Neurosurgery; Holden Comprehensive Cancer Center; Internal Medicine
Record Identifier: 9984066380202771

Metrics

37 Record Views

17 Times Cited - Web of Science

See more details