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-a (DGKa) has therapeutic potential
against GBM; we demonstrated direct actions on cancer cells and on angiogenesis, while others have
identified a role for DGKa in T cell reactivity. In addition, we identified an abandoned medication safe in
humans, ritanserin, as a novel DGKa 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 DGKa inhibition
involving bosting macrophage and microglia function, and also show synergistic activity in combining a DGKa
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
DGKa inhibitors on macrophages and microglia, testing a putative mechanism as well. It also tests the
hypothesis that the anti-mesenchymal activity of DGKa 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 DGKa 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 DGKa inhibition, alone and in combination, helping to place it in the
GBM armamentarium but with broader implications for oncology and other areas as well.