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

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 (Fe(3+)) catalyzes ascorbate's oxidation to form diamagnetic iron (Fe(2+)). Because paramagnetic Fe(3+) 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 Fe(3+) or Fe(2+) 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 Fe(3+) and Fe(2+) gel phantoms. A GBM mouse model was used to study the relationship between the imaging findings and the labile iron pool. Phantoms containing Fe(3+) demonstrated detectable changes in T2* and QSM relaxation times relative to Fe(2+) phantoms. Compared to pre-P-AscH(-), GBM T2* and QSM imaging were significantly changed post-P-AscH(-) infusion consistent with conversion of Fe(3+) to Fe(2+). 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 Fe(3+) to Fe(2+), 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.