In vivo chemical exchange saturation transfer imaging allows early detection of a therapeutic response in glioblastoma

Significance The prognosis and management of patients with glioma is vastly different depending on whether one detects tumor progression or treatment effects. Although the gold standard in the evaluation of treatment efficacy involves MRI, the currently available imaging methods often do not suffice to make the final decision. Our study demonstrated that amide proton transfer (APT) imaging, one subset of chemical exchange saturation transfer imaging, can detect molecular signals in glioma induced by short-term chemotherapy with temozolomide. These molecular events precede morphologic changes. The APT signal did not decrease in tumors resistant to chemotherapy. APT imaging may provide a useful prognostic biomarker of treatment response or tumor progression in glioma. Glioblastoma multiforme (GBM), which account for more than 50% of all gliomas, is among the deadliest of all human cancers. Given the dismal prognosis of GBM, it would be advantageous to identify early biomarkers of a response to therapy to avoid continuing ineffective treatments and to initiate other therapeutic strategies. The present in vivo longitudinal study in an orthotopic mouse model demonstrates quantitative assessment of early treatment response during short-term chemotherapy with temozolomide (TMZ) by amide proton transfer (APT) imaging. In a GBM line, only one course of TMZ (3 d exposure and 4 d rest) at a dose of 80 mg/kg resulted in substantial reduction in APT signal compared with untreated control animals, in which the APT signal continued to increase. Although there were no detectable differences in tumor volume, cell density, or apoptosis rate between groups, levels of Ki67 (index of cell proliferation) were substantially reduced in treated tumors. In another TMZ-resistant GBM line, the APT signal and levels of Ki67 increased despite the same course of TMZ treatment. As metabolite changes are known to occur early in the time course of chemotherapy and precede morphologic changes, these results suggest that the APT signal in glioma may be a useful functional biomarker of treatment response or degree of tumor progression. Thus, APT imaging may serve as a sensitive biomarker of early treatment response and could potentially replace invasive biopsies to provide a definitive diagnosis. This would have a major impact on the clinical management of patients with glioma.