Developing an image-guided therapeutic strategy to effectively target metabolic reprogramming in glioblastoma

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Project Summary Glioblastoma (GBM) cells reversibly switch their metabolic phenotype to adapt to changes in the microenvironment and sustain their growth. For this reason, targeting a single metabolic pathway is ineffective. One viable approach is to induce a shift towards a specific metabolic phenotype and then target the activated metabolic pathway. With our recent report in Neuro-Oncology, we demonstrated diacylglycerol kinase alpha (DGKα) as a novel therapeutic vulnerability in GBM. We showed that targeting DGKα with the clinically applicable DGKα inhibitor, ritanserin, significantly suppresses GBM growth in vitro and in vivo. DGKα has extensive interactions with the key mediators of cellular metabolism, including mTOR, NF-κB, and HIF-1α. Despite this, the role of DGKα in the regulation of metabolism has not been studied in GBM. Following up on our study, we preliminarily showed that DGKα functions as a crucial regulator of lipid metabolic pathways and that DGKα inhibition with ritanserin significantly suppresses lipid metabolism. The DGKα pathway is connected to glycolysis through multiple pathways. Supporting this crosstalk, our recent findings suggest that suppression of glucose metabolism leads to the activation of DGKα, and also that DGKα inhibition alone drives a metabolic switch towards increased glycolysis. We subsequently showed that the combination of ritanserin and lonidamine, a novel, clinically applicable inhibitor of glycolysis, exhibits significant synergy and cytotoxicity against GBM. We therefore propose to develop an image-guided therapeutic approach to effectively target energy metabolism in GBM. We aim to induce metabolic addiction to enhanced glycolysis through DGKα inhibition and determine the increase in glucose metabolism using a next-generation digital photon counting PET/CT imaging system. We will subsequently target the glycolytic pathway with lonidamine. We will study the following aims: Aim 1 will determine the role of DGKα to regulate lipid metabolism and Aim 2 will evaluate the metabolic switch towards increased glycolysis upon DGKα inhibition and will test the efficacy of the combined ritanserin and lonidamine treatment. Both lonidamine and ritanserin are orally bioavailable and have already been tested in clinical trials and proven safe in humans. Given the favorable pharmacologic features, including very good BBB penetration, if successful, the proposed combined treatment can be quickly transferred to the clinic for trials in patients with GBM and other cancers.