Purpose: Glioblastoma (GBM) is the most common primary CNS malignancy in adults. Despite aggressive standard therapy (radiotherapy and temozolomide), patient outcomes remain poor (OS=14.6 mos.). Pharmacological ascorbate (P-AscH-; IV vitamin C) has emerged as a novel, iron-dependent approach to enhance GBM therapy. The use of a non-invasive marker of iron content in tumors may provide insight into P-AscH- treatment responsiveness. T2* mapping is an MRI technique used clinically to detect iron and is inversely proportional to iron content. We evaluated the utility of T2* mapping to detect iron metabolism and predict GBM patient outcomes.
Methods: GBM cells were cultured in 21% O2 and all in vitro experiments were performed with exponentially growing cells. Cell viability was determined using clonogenic survival. Ferritin heavy chain (FtH) overexpression was done in U251 GBM cells by using a doxycycline-inducible FtH promoter containing lentivirus transduction. Cell pellets were embedded in 1% agarose gel for T2* analysis. T2* analysis was performed on human subjects (n = 52) enrolled in a phase II clinical trial evaluating P-AscH- in combination with temozolomide and radiation. T2* maps were generated using a multi-echo gradient-echo pulse sequence with a mono-exponential fit applied to the magnitude image set.
Results: We were able to show that T2* MRI is accurately able to detect changes in iron content resulting from genetic perturbations of iron metabolism in vitro. These changes in T2* are directly proportional to both the redox-active iron content of a cell and the cell viability following ascorbate therapy. T2* mapping can accurately detect iron sequestration by FtH and is strongly correlated with P-AscH- sensitivity in cell culture. In 52 enrolled subjects, initial T2* relaxation times were inversely correlated with OS.
Conclusion: T2* mapping shows significant promise as a non-invasive biomarker of GBM outcomes associated with P-AscH- therapy to allow for treatment personalization.
Not Applicable / None Entered.