There is a dire need for new treatment approaches to glioblastoma (GBM), a uniformly lethal brain cancer. We previously reported that targeting the lipid kinase Diacylglycerol kinase-α (DGKα) has therapeutic potential against GBM; we demonstrated direct actions on cancer cells and on angiogenesis, while others have identified a role for DGKα in T cell reactivity. In addition, we identified an abandoned medication safe in humans, ritanserin, as a novel DGKα inhibitor that can be repurposed to accelerate clinical translation of this therapeutic strategy. Our new preliminary data indicate in an immunocompetent mouse model of GBM that intermittent low dosing of ritanserin is dramatically more effective than similar cumulative doses done in a near- continuous fashion. Furthermore, other new data suggest a novel immunologic mechanism for DGKα inhibition involving bosting macrophage and microglia function, and also show synergistic activity in combining a DGKα inhibitor and anti-PD-1 checkpoint inhibition or temozolomide in mouse GBM models. This revised proposal focuses on developing these novel findings with three Specific Aims. The first Aim investigates the effects of DGKα inhibitors on macrophages and microglia, testing a putative mechanism as well. It also tests the hypothesis that the anti-mesenchymal activity of DGKα inhibition will reduce expression of immunosuppressive proteins in GBM cells. Aim 2 will dissect in syngeneic mouse models of GBM the immunologic and other effects of intermittent low dosing of DGKα inhibition, identifying mechanisms for its curative potential in mouse GBM and comparing treatment schedules. While our new data show striking efficacy of intermittent ritanserin in a mouse GBM model, we anticipate that combination therapy will be necessary to effectively treat GBM in patients; therefore Aim 3 tests combinations of intermittent ritanserin with other agents—anti-PD1 checkpoint inhibition and temozolomide—based on strong rationales and preliminary data. The most effective combination will be advanced for clinical investigation. Successful completion of the proposed studies will establish critical therapeutic and mechanistic aspects of DGKα inhibition, alone and in combination, helping to place it in the GBM armamentarium but with broader implications for oncology and other areas as well.

Glioblastoma (GBM) is the most common and lethal brain cancer, and there is a dire need for new therapeutic approaches. We previously showed that Diacylglycerol kinase-α (DGKα) is a potential therapeutic target for GBM, with DGKα inhibition having the exciting potential to directly attack cancer cells but possibly also boost the anti-tumor immune response. More recently we showed that the abandoned drug ritanserin could be repurposed as a DGKα inhibitor, potentially accelerating the clinical development of this strategy. Ritanserin has shown greater promise in combination with other agents. Our newest results show that intermittent dosing of ritanserin—with a low dose every two to three days—is extremely effective in a mouse model of GBM with an intact immune system. We have also found a potential new mechanism of DGKα inhibition in the immune system. This proposal will test the effects of DGKα inhibition on these immune cells, as well as following up on the mechanisms and activity of intermittent low dosing of DGKα inhibitors, alone and combined with other agents, in treating GBM in mouse models. The results should inform the clinical development of DGKα inhibition as a novel treatment for GBM and identify new mechanisms.