Novel immunotherapeutic potential of DGKalpha inhibition for glioblastoma

DGKα 抑制对胶质母细胞瘤的新免疫治疗潜力

基本信息

批准号：
10584015
负责人：
Benjamin W. Purow
金额：
$ 39.9万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-15 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10584015
关键词：
Acceleration Affect Aftercare Area Binding Biological Availability Biological Response Modifiers Brain Neoplasms CSF1R gene Cells Cessation of life Combined Modality Therapy Data Diacylglycerol Kinase Dichloromethylene Diphosphonate Diglycerides Dose Family Family member Glioblastoma Grant Half-Life Hour Human Immune Immune system Immunity Immunocompetent Immunologic Deficiency Syndromes Immunologics Immunotherapeutic agent Immunotherapy In Vitro Inflammatory Knockout Mice Ligands Lipids Liposomes Literature Macrophage Malignant Neoplasms Malignant neoplasm of brain Mediating Mesenchymal Microglia Modeling Mus Natural Killer Cells Oncology Operative Surgical Procedures Oral Orphan Drugs PD-1 inhibitors Patients Pharmaceutical Preparations Phenotype Phosphatidic Acid Phosphotransferases Physiologic pulse Positioning Attribute Primary Brain Neoplasms Protein Isoforms Proteins Radiation Receptor Inhibition Refractory Regimen Regulation Reporting Resistance Ritanserin Role Stimulus T cell anergy T-Lymphocyte Testing Therapeutic Toxic effect Treatment Protocols Wild Type Mouse angiogenesis anti-PD-1 anti-PD1 antibodies anti-tumor immune response blood-brain barrier penetration cancer cell checkpoint inhibition chemotherapy clinical development clinical investigation clinical translation cytokine exhaustion follow-up immune checkpoint improved in vitro testing in vivo inhibitor member mouse model novel novel therapeutic intervention pharmacologic programmed cell death ligand 1 protein geranylgeranyltransferase restraint serotonin receptor targeted treatment temozolomide therapeutic target translational therapeutics treatment comparison

项目摘要

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.

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。先前报道，靶向脂质激酶二酰甘油激酶-α (DGKα) 具有治疗潜力对抗 GBM；我们证明了对癌细胞和血管生成的直接作用，而其他人则证明了这一点确定了 DGKα 在 T 细胞反应中的作用此外，我们还确定了一种废弃药物的安全性。利坦色林（ritanserin）作为一种新型 DGKα 抑制剂，可以重新利用以加速该药物的临床转化我们新的初步治疗数据表明，在免疫功能正常的 GBM 小鼠模型中，间歇性低剂量利坦色林比近年类似的累积剂量更有效。此外，其他新数据表明了 DGKα 抑制的新免疫机制。增强巨噬细胞和小胶质细胞的功能，并在组合 DGKα 时表现出协同活性小鼠 GBM 模型中的抑制剂和抗 PD-1 检查点抑制或替莫唑胺。重点是通过三个具体目标来开发这些新颖的发现，第一个目标是调查以下因素的影响。 DGKα 抑制剂对巨噬细胞和小胶质细胞的作用，也测试了一种假定的机制。假设 DGKα 抑制的抗间充质活性会减少免疫抑制的表达目标 2 将在 GBM 的同基因小鼠模型中剖析免疫学和其他方面的蛋白质。间歇性低剂量 DGKα 抑制的效果，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在治疗中具有惊人的功效。在小鼠 GBM 模型中，我们预计联合疗法对于有效治疗 GBM 是必要的因此，Aim 3 测试了间歇性利坦色林与其他药物（抗 PD1 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。将推进临床研究，成功完成拟议的研究将建立关键的基础。 DGKα 抑制的治疗和机制方面，单独或组合，有助于将其置于 GBM 武器库，但对肿瘤学和其他领域也具有更广泛的影响。