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.

神经肿瘤学的两个最大挑战是胶质母细胞瘤原发性脑肿瘤的治疗和黑色素瘤脑转移都可以用放射治疗和替莫唑胺治疗，但这充其量只是治疗。 GBM 和黑色素瘤均具有显着的遗传特征，可延缓这些癌症的进展。异质性和适应靶向治疗的能力该项目试图解决这两个问题。通过针对癌症中的新型信号转导中心，二酰甘油激酶 α (DGKα)，我们之前进行了研究。 microRNA 对 GBM 细胞具有细胞毒性，使我们确定 DGKα 的敲低是其细胞毒性的主要驱动因素，表明针对该激酶及其产物磷脂酸的潜在效用已被研究。发现在许多具有致癌作用的信号通路中很重要，进一步支持了 DGKα 的潜力我们最近报道了 DGKα 的敲低和小分子抑制会导致细胞凋亡。这些研究还表明，GBM 和黑色素瘤细胞系在体外和小鼠模型中都会死亡。体内抗血管生成作用以及 mTOR 和 HIF-1α 作为 DGKα 作用介质的重要性自从我们发表报告以来，我们发现以前发现的一种废弃药物是安全的。重要的是，最近有报道称，利坦色林是一种新型 DGKα 抑制剂，用于非癌症适应症的临床试验。表明 DGKα 抑制剂有可能打破 T 细胞无反应性并增强癌症免疫疗法。因此，我们发现利坦色林和其他新型 DGKα 抑制剂将非常有效地对抗 GBM 和黑色素瘤脑转移，既可作为单一药物，也可与免疫疗法联合治疗。在这个提案中，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，并评估可能的耐药机制。目标 2 将研究利坦色林和其他新型 DGKα 抑制剂对于 GBM 和其他疾病是否安全有效在目标 3 中，我们将确定免疫功能正常的小鼠是否存在这些黑色素瘤小鼠异种移植模型。 DGKα 抑制剂可增强局部免疫反应，并与免疫疗法产生协同作用。拟议研究的完成将揭示 DGKα 在 GBM 中的生物学和治疗靶向和黑色素瘤脑转移，这种策略可能具有快速转化为临床试验的潜力。在癌症中具有广泛的适用性，通过对癌细胞的直接细胞毒性、抗血管生成作用以及增强一系列有前途的新免疫疗法。