Targeting diacylglycerol kinases in glioblastoma

描述（由申请人提供）：胶质母细胞瘤（GBM）是最常见、最致命的脑肿瘤，对手术、放疗和化疗等标准治疗具有耐药性。这种抗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；2)干细胞样的“GBM干细胞”亚群，似乎产生了大部分癌细胞，并且是特别顽固的靶标。本项目试图通过靶向癌症中的新型信号枢纽二酰基甘油激酶（DGKs）来解决这两个问题。我们之前对一种对GBM细胞有细胞毒性的microRNA的研究使我们鉴定出它对DGK？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。DGK吗?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起重要作用，进一步支持DGKs作为靶点的潜力。我们最近报道了DGK？在体外和小鼠模型中，在GBM和GSC系以及其他癌症中引起凋亡细胞死亡。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？对癌症的影响。自先前提交此申请和我们发表的报告以来，我们发现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抑制剂。我们假设DGKs是GBM中有希望的治疗靶点，并且重新利用利坦色林将允许该策略的快速临床转化。这一假设将与拟议的研究一起深入研究。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？角色在DGK家族成员中是独一无二的。目的2将测试利坦色林和已建立的DGK？GSCs的抑制主要是通过抑制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将评估通过缓释泵或涉及聚合物包被微泡/聚焦超声的创新技术给药DGK抑制剂是否能达到更大的疗效。这些研究的成功完成将揭示DGKs在GBM中的生物学和治疗靶向性，并有可能快速转化为临床试验。这种策略可能在癌症中具有广泛的适用性，对癌细胞具有直接的细胞毒性，抗血管生成作用，并增强其他治疗；最近的报道表明，抑制DGK是一种很有希望的增强癌症免疫治疗的方法。

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.