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：
8786709
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/8786709
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 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 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 human FRAP1 protein in vivo inhibitor/antagonist innovation kinase inhibitor melanoma mouse model neuro-oncology neuroimmunology novel pre-clinical public health relevance resistance mechanism response small molecule standard care 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。二酰甘油激酶 ¿ (DGK¿)。我们之前对 microRNA 对 GBM 细胞的细胞毒性的研究使我们确定了它对 DGK 的敲低。作为其细胞毒性的主要驱动因素，表明靶向该激酶的潜在效用。其产品磷脂酸已被发现在许多具有致癌作用的信号通路中发挥重要作用，进一步支持了 DGK 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，这些研究还表明了 mTOR 和 HIF-1 的重要性以及体内的抗血管生成作用。作为 DGK 的调解人??自从我们发表报告以来，我们发现一种在先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¿重要的是，最近的报告表明 DGK¿抑制剂有可能打破 T 细胞无反应性并增强癌症免疫疗法，因此我们对利坦色林和其他新型 DGK 进行了争夺。抑制剂对于 GBM 和黑色素瘤脑转移都非常有效，无论是作为单一药物还是与免疫疗法联合使用，在该提案的目标 1 中，我们将测试假定的新型 DGK 的效果。目标 2 将研究利坦色林和其他新型 DGK 是否会影响 GBM 和黑色素瘤细胞表型的抑制剂，并评估可能的耐药机制。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 是否有效。抑制剂可增强局部免疫反应并与免疫疗法具有协同作用，拟议研究的成功完成将为 DGK 的生物学和治疗靶向提供线索。在 GBM 和黑色素瘤脑转移中，这种策略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来发挥作用。