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：
9111671
负责人：
Benjamin W. Purow
金额：
$ 49.36万
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 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9111671
关键词：
Address Affect Angiogenesis Inhibitors Apoptosis Apoptotic Automobile Driving Bioavailable Biological Models Biology Blood Blood - brain barrier anatomy Brain Brain Neoplasms C57BL/6 Mouse CTLA4-Ig Cell Count Cell Death Cells Clinic Clinical Clinical Trials Data Development Diacylglycerol Kinase Enzymes FRAP1 gene Family member Flow Cytometry Genetic Genetic Heterogeneity Genetically Engineered Mouse Glioblastoma Glioma Half-Life Health 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 malignant neoplasm to brain Metastatic to MicroRNAs Microglia Modeling Mus Neoplasm Metastasis Oncogenic Operative Surgical Procedures Ovalbumin Pathway interactions Patients Pharmaceutical Preparations 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 bryostatin c-myc Genes cancer cell cancer immunotherapy chemotherapy cytotoxic cytotoxicity experience hypoxia inducible factor 1 in vivo inhibitor/antagonist innovation kinase inhibitor knock-down melanoma mouse model neuro-oncology neuroimmunology novel overexpression pre-clinical radioresistant resistance mechanism response small molecule small molecule inhibitor standard care targeted treatment temozolomide therapeutic target tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): 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 � (DGK�). Our prior studies of a microRNA cytotoxic to GBM cells led us to identify its knockdown of DGK� as a major driver of its cytotoxicity, indicating the potential utility of targeting this kinase. DGK� ad its product phosphatidic acid had already been found important in numerous signaling pathways with oncogenic roles, further supporting the potential of DGK� as a target. We recently reported that knockdown and small-molecule inhibition of DGK� 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-1� as mediators of DGK� 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 DGK� inhibitor. Importanty, recent reports suggest that DGK� inhibitors have the potential to break T cell anergy and boost cancer immunotherapies. We therefore hypothesize that ritanserin and other novel DGK� 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 DGK� 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 DGK� inhibitors are safe and effective in GBM and melanoma mouse xenograft models. In Aim 3, we will determine in immnocompetent mice whether these DGK� 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 DGK� in GBM and melanoma brain metastases, with the potential for rapid translation to clinical trials. This strategy may have broad applicabiity in cancer, acting via direct cytotoxicity to cancer cells, antiangiogenic effects, and enhancing a host of promising new immunotherapies.

描述（由适用提供）：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和黑色素瘤脑转移的治疗。两者都可以用辐射和替莫唑胺处理，但充其量仅延迟了这些癌症的进展。 GBM和黑色素瘤均以实质性的遗传异质性和适应靶向疗法的能力为特征。该项目试图通过针对癌症，二酰基甘油激酶（DGK）的新信号中心来解决这两个问题。我们先前对MicroRNA细胞毒性对GBM细胞的研究使我们确定了其DGK的敲低是其细胞毒性的主要驱动力，这表明靶向这种激酶的潜在效用。 DGK AD的产物磷脂酸已经被发现在具有致癌作用的众多信号通路中很重要，从而进一步支持DGK作为靶标的潜力。我们最近报道，在体外和小鼠模型中，敲低和小分子抑制DGK会导致GBM和黑色素瘤系的凋亡细胞死亡。这些研究还表明，体内的抗血管生成作用以及MTOR和HIF-1作为DGK效应在癌症中的重要性。自从我们发表的报告以来，我们发现一种在先前的非癌症指示的临床试验中发现的废弃药物是一种新型的DGK抑制剂。重要的是，最近的报道表明，DGK抑制剂有可能破坏T细胞消极并增强癌症免疫疗法。因此，我们假设利坦塞蛋白和其他新型的DGK抑制剂将对来自黑色素瘤的GBM和脑转移非常有效，无论是单一药物还是与免疫疗法结合使用。在该提案的目标1中，我们将测试假定的新型DGK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。 AIM 2将研究利坦塞蛋白和其他新型DGK抑制剂是否在GBM和黑色素瘤小鼠的元素模型中安全有效。在AIM 3中，我们将在免疫能力的小鼠中确定这些DGK抑制剂是否会增加局部免疫反应并与免疫疗法协同作用。拟议研究的成功完成将揭示DGK在GBM和黑色素瘤脑转移酶中的生物学和治疗靶向，并有可能快速转化为临床试验。该策略可能在癌症中广泛适用，通过直接细胞毒性对癌细胞，抗血管生成作用，并增强了许多有希望的新免疫疗法。