Targeting diacylglycerol kinases in glioblastoma

靶向胶质母细胞瘤中的二酰甘油激酶

基本信息

批准号：
8709072
负责人：
Benjamin W. Purow
金额：
$ 40.85万
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：
2014-05-06 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8709072
关键词：
Address Angiogenesis Inhibitors Apoptosis Apoptotic Attention Bioavailable Biological Markers Biology Blood - brain barrier anatomy Brain Neoplasms Cancer Patient Cell Death Cell Differentiation process Cell Line Cell Survival Cells Clinic Clinical Clinical Trials Complement Data Diacylglycerol Kinase Dose Drug Kinetics Family Family member Focused Ultrasound Therapy Genes Genetic Heterogeneity Genetic Variation Genetically Engineered Mouse Glioblastoma Glioma Half-Life Hour Human Immunotherapy In Vitro Individual Light Malignant Neoplasms Mediating Mediator of activation protein MicroRNAs Microbubbles Modality Modeling Molecular Mus Mutation Oncogenic Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Phenotype Phosphatidic Acid Phospholipids Phosphotransferases Play Polymers Population Proteins Publishing Pump Radiation Radiosurgery Reporting Resistance Ritanserin Role Safety Serum Signal Pathway Signal Transduction Solid Source Stem cells Techniques Testing Therapeutic Toxic effect Transgenic Mice Translations Up-Regulation Work Xenograft procedure addiction analog angiogenesis c-myc Genes cancer cell cancer immunotherapy cancer therapy chemotherapy combinatorial cytotoxic cytotoxicity experience expression vector human FRAP1 protein improved in vivo inhibitor/antagonist innovation kinase inhibitor mTOR inhibition mouse model novel public health relevance small molecule standard care stem subcutaneous temozolomide therapeutic target tumor

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma (GBM) is the most common and lethal brain tumor, with resistance to standard treatments such as surgery, radiation, and chemotherapy. This resistance stems in large part from two sources: 1) genetic heterogeneity that lets it survive inhibition of single signaling pathways and 2) a stem cell-like subpopulation f "GBM stem cells" (GSCs) that appear to generate the bulk of the cancer cells and are particularly stubborn targets. This Project attempts to address both problems through targeting novel signaling hubs in cancer, the diacylglycerol kinases (DGKs). 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? and its product phosphatidic acid had already been found important in numerous signaling pathways with oncogenic roles, further supporting the potential of DGKs as targets. We recently reported that knockdown and small-molecule inhibition of DGK? causes apoptotic cell death in GBM and GSC lines, as well as in other cancers, 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 the prior submission of this application and 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. We hypothesize that the DGKs are promising therapeutic targets in GBM, and that repurposing ritanserin will allow rapid clinical translation of this strategy. This hypothesis will be investigated in depth with the proposed studies. In Aim 1, we will assess whether multiple DGKs have important overlapping functions in GSCs, and whether the DGK? role is unique among DGK family members. Aim 2 will test if the effects of ritanserin and an established DGK? inhibitor on GSCs are mediated largely by inhibition of mTOR and HIF-1?. The studies of Aim 3 will determine pharmacokinetics, safety, and efficacy of ritanserin in GSC xenografts and a transgenic mouse model of high-grade glioma, while Aim 4 will evaluate whether even greater efficacy can be achieved with delivery of DGK inhibitors by a sustained-release pump or by an innovative technique involving polymer-coated microbubbles/focused ultrasound. Successful completion of the proposed studies will shed light on the biology and therapeutic targeting of the DGKs in GBM, with the potential for rapid translation to clinical trials. This strategy may have broad applicability in cancer, acting ia direct cytotoxicity to cancer cells, antiangiogenic effects, and enhancement of other therapies; recent reports indicate that DGK inhibition is a promising approach to enhancing cancer immunotherapy.

描述（由申请人提供）：胶质母细胞瘤（GBM）是最常见和致命的脑肿瘤，对诸如手术，放射和化学疗法等标准治疗的耐药性。这种耐药性很大程度上来自两个来源：1）遗传异质性，使其能够在单个信号通路抑制它的抑制和2）干细胞样亚群F“ GBM干细胞”（GSC）（GSC）（GSC）（GSC）似乎会产生大量癌细胞，并且特别是顽固的靶标。该项目试图通过靶向癌症中的新信号枢纽，二酰基甘油激酶（DGKS）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？作为其细胞毒性的主要驱动力，表明靶向这种激酶的潜在效用。 DGK？它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。我们最近报道了DGK的敲低和小分子抑制作用？导致GBM和GSC系中的凋亡细胞死亡，以及其他癌症的体外和小鼠模型中的凋亡细胞死亡。这些研究还表明，体内的抗血管生成作用以及MTOR和HIF-1的重要性？作为DGK的调解人？对癌症的影响。自从此应用程序和我们已发表的报告事先提交以来，我们发现一种废弃的药物在先前针对非癌症指示的临床试验中发现了安全的药物，Ritanserin是一种新颖的DGK抑制剂。我们假设DGK是GBM中有希望的治疗靶标，而重新利用利坦塞林将允许快速临床翻译此策略。该假设将通过拟议的研究深入研究。在AIM 1中，我们将评估多个DGK在GSC中是否具有重要的重叠功能，以及DGK是否具有？角色在DGK家庭成员中是独一无二的。 AIM 2会测试利坦塞林和已建立的DGK的影响？ GSC上的抑制剂主要是通过抑制MTOR和HIF-1？介导的。 The studies of Aim 3 will determine pharmacokinetics, safety, and efficacy of ritanserin in GSC xenografts and a transgenic mouse model of high-grade glioma, while Aim 4 will evaluate whether even greater efficacy can be achieved with delivery of DGK inhibitors by a sustained-release pump or by an innovative technique involving polymer-coated microbubbles/focused ultrasound.拟议研究的成功完成将揭示DGK在GBM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具有广泛的适用性，对IA直接细胞毒性作用于癌细胞，抗血管生成作用以及其他疗法的增强。最近的报道表明，DGK抑制是一种增强癌症免疫疗法的有前途的方法。