DDIS-05. TARGETING MESENCHYMAL GLIOBLASTOMA THROUGH INHIBITION OF DIACYLGLYCEROL KINASE ALPHA

Abstract

Recent studies have shown that glioblastoma (GBM) can be classified into distinct subtypes based on gene expression signatures: classical, proneural, and mesenchymal. Of these, the mesenchymal subtype is relatively more aggressive and resistant to therapy, and is thought to be a primary driver of recurrence. The diacylglycerol kinase alpha (DGKα) signaling pathway has extensive connections to oncogenic pathways/proteins. Recently, we identified ritanserin, an abandoned serotonin receptor 5-HT2 inhibitor originally developed for schizophrenia, as a novel DGKα inhibitor. Compared to a known DGKα inhibitor, R59022, ritanserin is more potent and has favorable pharmacologic features such as long plasma half-life and known BBB penetration. Based on the TCGA database, we have determined that DGKα expression level is highest in the mesenchymal subtype. DGKα inhibition with ritanserin revealed a significant difference in IC50 values, with a 3-4 fold increase in sensitivity, of all mesenchymal GBM stem cell (GSC) lines tested versus all non-mesenchymal lines. In vivo, daily oral ritanserin increased mice survival significantly with two mesenchymal GSC lines, while there was no survival benefit with a proneural GSC line. With an EMT model, both lung and pancreatic carcinoma cells became more sensitive to ritanserin after the acquisition of mesenchymal phenotype. Ritanserin reduces NF-κB activity significantly and suppresses geranylgeranylation of proteins by inhibiting geranylgeranyltransferase I. Exogenous phosphatidic acid, the DGKα enzymatic product, substantially rescued GBM cells from ritanserin toxicity while exogenous 5-HT2 receptor agonist, 5-hydroxytryptamine, showed a small rescue from ritanserin toxicity. In keeping with its anti-mesenchymal activity, ritanserin functions as a radiosensitizer, with suppression of the DNA damage response and shows significant synergy with radiation. Our work is the first to show in vitro and in vivo that a clinically practical agent has strong preferential toxicity for the mesenchymal GBM subtype, with potential therapeutic implications for GBM and other cancers as well.