Novel immunotherapeutic potential of DGKalpha inhibition for glioblastoma

胶质母细胞瘤（GBM）是一种致命的脑癌，迫切需要新的治疗方法。我们 先前报道，靶向脂质激酶二酰甘油激酶-α（DGKα）具有治疗潜力 我们证明了对癌细胞和血管生成的直接作用，而其他人则 确定了DGKα在T细胞反应性中的作用。此外，我们发现了一种废弃的药物， 人类，利坦色林，作为一种新型的DGKα抑制剂，可以重新利用，以加速临床翻译，这是一个新的研究领域。 治疗策略我们新的初步数据表明，在免疫活性小鼠GBM模型中， 间歇性低剂量的利坦色林比在近- 连续的方式。此外，其他新的数据表明，一种新的免疫机制，抑制DGKα 包括增强巨噬细胞和小胶质细胞的功能，并在结合DGKα 抑制剂和抗PD-1检查点抑制或替莫唑胺。这一订正提案 专注于开发这些具有三个特定目标的新发现。第一个目的是研究 巨噬细胞和小胶质细胞上的DGKα抑制剂，也测试了假定的机制。更考验 假设DGKα抑制的抗间充质活性将减少免疫抑制因子的表达， GBM细胞中的蛋白质。目的2将在同系小鼠GBM模型中解剖免疫学和其他 间歇性低剂量DGKα抑制的影响，确定其在小鼠中的治疗潜力的机制 GBM和比较治疗方案。虽然我们的新数据显示间歇性利坦色林对 在小鼠GBM模型中，我们预期联合治疗对于有效治疗GBM是必要的。 患者;因此，Aim 3测试了间歇性利坦色林与其他药物-抗PD 1检查点的组合 抑制和替莫唑胺-基于强有力的理由和初步数据。最有效的组合 将推进临床研究。成功完成拟议的研究将建立关键的 DGKα抑制的治疗和机制方面，单独和组合，有助于将其置于 GBM医疗设备，但对肿瘤学和其他领域也有更广泛的影响。

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.