Research Plan Summary: Jonathan David Dewey

Project Title: The effects of monocarboxylate transporter-1 inhibition on glioblastoma metabolism and viability in vivo.

Glioblastoma multiforme (GBM) is the most common and deadly primary neoplasm of the central nervous system in adults. Even after optimal therapy, more than fifty percent of patients with GBM die within one year of diagnosis. We have recently identified a metabolic symbiosis between hypoxic and normoxic tumor regions that may contribute to the resilience of high grade tumors like GBM. Well-oxygenated tumor cells preferentially oxidize lactate, which is produced by hypoxic tumor cells as the end product of glycolysis. Monocarboxylate transporter 1 (MCT1) is responsible for lactate transportation and is the gatekeeper of this symbiotic relationship. Inhibition of MCT1 has proven to be an effective antitumor strategy in several tumor models. Although MCT1 expression is positively correlated with tumor grade in gliomas, the effects of MCT1 inhibition have not been studied in CNS tumors in vivo. We propose to evaluate the therapeutic efficacy of MCT1 inhibition in glioblastoma using the GBM6 glioma model, transplanted into the basal ganglia of nude mice. To accomplish this goal, we propose the following specific aims:

1. Assess the effects of MCT1 inhibition on tumor lactate concentrations in vivo.
2. Determine the spatiotemporal relationship between lactate concentrations, hypoxia, and tumor cell necrosis.
3. Evaluate the accuracy of selective saturation transfer MRI in measuring intracranial lactate concentrations.