Targeting diacylglycerol kinases in glioblastoma

靶向胶质母细胞瘤中的二酰甘油激酶

• 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
• 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

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，对手术、放疗和化疗等标准治疗具有抵抗力。这种耐药性在很大程度上源于两个来源：1）遗传异质性使其能够在单一信号通路的抑制下存活下来；2）“GBM干细胞”（GSC）的干细胞样亚群，它似乎能产生大量癌细胞，并且是特别顽固的目标。该项目试图通过针对癌症中的新型信号转导中心二酰甘油激酶 (DGK) 来解决这两个问题。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。德格克？其产物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 作为靶点的潜力。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，导致 GBM 和 GSC 系以及其他癌症中的细胞凋亡。这些研究还表明了体内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。自从之前提交本申请和我们发表的报告以来，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。我们假设 DGK 是 GBM 有希望的治疗靶点，并且重新利用利坦色林将允许该策略快速临床转化。该假设将通过拟议的研究进行深入调查。在目标 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？在 DGK 家族成员中，这一角色是独一无二的。目标 2 将测试利坦色林和已建立的 DGK 是否有效果？ GSC 上的抑制剂主要是通过抑制 mTOR 和 HIF-1? 介导的。 Aim 3 的研究将确定利坦色林在 GSC 异种移植物和高级别神经胶质瘤转基因小鼠模型中的药代动力学、安全性和有效性，而 Aim 4 的研究将评估通过缓释泵或涉及聚合物涂层微泡/聚焦超声的创新技术输送 DGK 抑制剂是否可以实现更大的疗效。拟议研究的成功完成将揭示 GBM 中 DGK 的生物学和治疗靶向，并具有快速转化为临床试验的潜力。该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其他疗法发挥作用；最近的报告表明，DGK 抑制是增强癌症免疫治疗的一种有前途的方法。