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：
9320518
负责人：
Benjamin W. Purow
金额：
$ 49.09万
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/9320518
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 bryostatin c-myc Genes cancer cell cancer immunotherapy chemotherapy clinical translation cytotoxic cytotoxicity experience hypoxia inducible factor 1 in vivo inhibitor/antagonist innovation kinase inhibitor knock-down melanoma mouse model neuro-oncology neuroimmunology novel overexpression preclinical development public health relevance 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（由申请人提供）：神经肿瘤学中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，这两种肿瘤都可以用放射和替莫唑胺治疗，但最多只能延缓这些癌症的进展。 GBM 和黑色素瘤都具有显着的遗传异质性和适应靶向治疗的能力，该项目试图通过针对癌症的新型信号中枢来解决这两个问题。我们之前对一种 microRNA 对 GBM 细胞具有细胞毒性的研究表明，DGK 的敲低是其细胞毒性的主要驱动因素，这表明靶向该激酶及其产物磷脂的潜在效用。已经发现 DGK 在许多具有进一步致癌作用的信号通路中发挥着重要作用，支持 DGK 作为靶标的潜力。我们最近报道了 DGK 的敲低和小分子抑制。在体外和小鼠模型中，这些研究还表明 mTOR 和 HIF-1 作为 DGK 在癌症中的作用介质的重要性。我们发现，在之前的非癌症适应症临床试验中发现安全的废弃药物利坦色林是一种新型 DGK 抑制剂。重要的是，最近的报告表明 DGK 抑制剂有可能破坏 T。因此，我们追求利坦色林和其他新型 DGK 抑制剂无论是作为单一药物还是与免疫疗法联合使用，都能够高度有效地对抗 GBM 和黑色素瘤脑转移。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，目标 2 将研究是否。利坦色林和其他新型 DGK® 抑制剂在 GBM 和黑色素瘤小鼠异种移植模型中是安全有效的。在目标 3 中，我们将在免疫功能正常的小鼠中确定这些 DGK® 抑制剂是否会增加局部免疫反应并与免疫治疗成功完成。研究将揭示 DGK® 在 GBM 和黑色素瘤脑转移中的生物学和治疗靶向，并有可能快速转化为临床试验。可能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许多有前途的新型免疫疗法发挥作用。