Novel DGKalpha inhibitors and immunotherapy for GBM and melanoma brain metastasis

用于 GBM 和黑色素瘤脑转移的新型 DGKα 抑制剂和免疫疗法

基本信息

批准号：
9649402
负责人：
Benjamin W. Purow
金额：
$ 5.86万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9649402
关键词：
Address Affect Angiogenesis Inhibitors Apoptosis Apoptotic Automobile Driving Bioavailable Biological Models Biology Blood Blood - brain barrier anatomy Blood Vessels Brain Brain Glioblastoma Brain Neoplasms C57BL/6 Mouse CTLA4-Ig Cell Count Cell Death Cells Clinic Clinical Trials Data Diacylglycerol Kinase Enzymes FRAP1 gene Family member Flow Cytometry Genetic Genetic Heterogeneity Genetically Engineered Mouse Glioblastoma Glioma Half-Life Heterogeneity Hour Human Image Immune response Immunocompetent Immunotherapy In Vitro Ketanserin Life Light Malignant Neoplasms Malignant neoplasm of brain Mediating Mediator of activation protein Melanoma Cell Metastatic Melanoma Metastatic malignant neoplasm to brain Metastatic to MicroRNAs Microglia Modeling Mus Neoplasm Metastasis Oncogenic Operative Surgical Procedures Oral Ovalbumin Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phenotype Phosphatidic Acid Phospholipids Phosphotransferases Primary Brain Neoplasms Property Proteins Publishing Radiation Reporting Resected Resistance Ritanserin Role SCID Mice Safety Signal Pathway Signal Transduction Stem cells T cell anergy T-Lymphocyte Testing Therapeutic Toxic effect Transgenic Organisms Translations Transplantation Work Xenograft Model Xenograft procedure activity marker addiction analog angiogenesis anti-PD-1 bryostatin c-myc Genes cancer cell cancer immunotherapy chemotherapy clinical translation cytotoxic cytotoxicity experience in vivo inhibitor/antagonist innovation knock-down melanoma mouse model neuro-oncology neuroimmunology novel overexpression overtreatment preclinical development radioresistant resistance mechanism response small molecule small molecule inhibitor standard care targeted treatment temozolomide therapeutic target tumor tumor progression

项目摘要

Two of the greatest challenges in neuro-oncology are the treatment of glioblastoma primary brain tumors and melanoma brain metastases. Both may be treated with radiation and temozolomide, but at best this merely delays the progression of these cancers. Both GBM and melanoma are marked by substantial genetic heterogeneity and by the ability to adapt to targeted therapies. This Project attempts to address both problems through targeting a novel signaling hub in cancer, diacylglycerol kinase α (DGKα). Our prior studies of a microRNA cytotoxic to GBM cells led us to identify its knockdown of DGKα as a major driver of its cytotoxicity, indicating the potential utility of targeting this kinase. DGKα and its product phosphatidic acid had already been found important in numerous signaling pathways with oncogenic roles, further supporting the potential of DGKα as a target. We recently reported that knockdown and small-molecule inhibition of DGKα causes apoptotic cell death in GBM and melanoma lines, both in vitro and in mouse models. These studies also indicated antiangiogenic effects in vivo and the importance of mTOR and HIF-1α as mediators of DGKα effects in cancer. Since our published report, we have discovered that an abandoned medication found safe in prior clinical trials for a non-cancer indication, ritanserin, is a novel DGKα inhibitor. Importantly, recent reports suggest that DGKα inhibitors have the potential to break T cell anergy and boost cancer immunotherapies. We therefore hypothesize that ritanserin and other novel DGKα inhibitors will be highly effective against GBM and brain metastases from melanoma, both as single agents and in combination with immunotherapy. In Aim 1 of this proposal, we will test the effects of putative novel DGKα inhibitors on GBM and melanoma cell phenotype, whether these compounds affect other DGK family members, and assess possible resistance mechanisms. Aim 2 will investigate whether ritanserin and other novel DGKα inhibitors are safe and effective in GBM and melanoma mouse xenograft models. In Aim 3, we will determine in immnocompetent mice whether these DGKα inhibitors increase the local immune response and are synergistic with immunotherapy. Successful completion of the proposed studies will shed light on the biology and therapeutic targeting of DGKα in GBM and melanoma brain metastases, with the potential for rapid translation to clinical trials. This strategy may have broad applicability in cancer, acting via direct cytotoxicity to cancer cells, antiangiogenic effects, and enhancing a host of promising new immunotherapies.

神经肿瘤学中最大的两个挑战是治疗胶质母细胞瘤原发性脑肿瘤和黑色素瘤脑转移。两者都可以用辐射和替莫唑胺处理，但充其量仅仅是延迟这些癌症的进展。 GBM和黑色素瘤都以实质性通用为标志异质性和适应靶向疗法的能力。该项目试图解决这两个问题通过靶向癌症中的新信号枢纽，二酰基甘油激酶α（DGKα）。我们先前对 MicroRNA细胞毒性对GBM细胞的细胞导致我们确定其对DGKα的敲低是其细胞毒性的主要驱动力，即表明靶向这种激酶的潜在效用。 DGKα及其产物磷脂酸已经是发现在众多具有致癌作用的信号通路中很重要，进一步支持了DGKα的潜力作为目标。我们最近报告说，DGKα的敲低和小分子抑制会导致凋亡细胞在体外和小鼠模型中，GBM和黑色素瘤系的死亡。这些研究也表明体内的抗血管生成作用以及MTOR和HIF-1α作为DGKα效应的介体的重要性癌症。自我们发表的报告以来，我们发现一种废弃的药物在先前发现安全非癌症指示ritanserin的临床试验是一种新型的DGKα抑制剂。重要的是，最近的报告表明DGKα抑制剂有可能破坏T细胞消极并增强癌症免疫疗法。我们因此，假设利坦塞蛋白和其他新型DGKα抑制剂将对GBM非常有效，并且来自黑色素瘤的脑转移，无论是单一药物，都与免疫疗法结合使用。在目标1中该提案，我们将测试假定的新型DGKα抑制剂对GBM和黑色素瘤细胞表型的影响，这些化合物是否影响其他DGK家族成员，并评估可能的抗性机制。 AIM 2将研究利坦塞林和其他新型的DGKα抑制剂是否在GBM中安全有效，并且黑色素瘤鼠标特色模型。在AIM 3中，我们将在Immnoctent小鼠中确定这些是否 DGKα抑制剂增加了局部免疫响应，并与免疫疗法协同作用。成功的拟议的研究的完成将阐明GBM中DGKα的生物学和治疗靶向和黑色素瘤脑转移，有可能快速转化为临床试验。这个策略可能有在癌症中的广泛适用性，通过直接细胞毒性对癌细胞起作用，抗血管生成作用并增强许多新的免疫疗法承诺。