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
Affiliations
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; Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IA, USA; Holden Comprehensive Cancer Center, Iowa City, IA, USA; Veterans Affairs Medical Center, 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; Corresponding author. Department of Radiation Oncology, 200 Hawkins Drive, 01621, PFPW, Iowa City, IA, 52242, USA.
Vincent A. Magnotta
Department of Radiology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, USA; Corresponding author. Department of Radiology, L311 PBDB, 169 Newton Road, Iowa City, IA, 52242, USA.
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. Conclusions: 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.
