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
(DGKa) as a novel therapeutic vulnerability in GBM. We showed that targeting DGKa with the clinically applicable
DGKa inhibitor, ritanserin, significantly suppresses GBM growth in vitro and in vivo. DGKa has extensive
interactions with the key mediators of cellular metabolism, including mTOR, NF-¿B, and HIF-1a. Despite this,
the role of DGKa in the regulation of metabolism has not been studied in GBM. Following up on our study, we
preliminarily showed that DGKa functions as a crucial regulator of lipid metabolic pathways and that DGKa
inhibition with ritanserin significantly suppresses lipid metabolism. The DGKa 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 DGKa, and also that DGKa 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 DGKa 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 DGKa to regulate lipid metabolism and Aim 2 will evaluate the metabolic switch towards
increased glycolysis upon DGKa 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.