Developing an image-guided therapeutic strategy to effectively target metabolic reprogramming in glioblastoma

项目摘要 胶质母细胞瘤（GBM）细胞可逆地转换其代谢表型，以适应细胞周期的变化。 微环境，促进其成长。因此，靶向单一代谢途径是无效的。 一种可行的方法是诱导向特定代谢表型的转变，然后靶向活化的 代谢途径我们最近在《神经肿瘤学》上发表的报告显示， (DGKα）作为GBM的一种新的治疗脆弱性。我们发现，用临床适用的靶向DGKα， DGKα抑制剂利坦色林在体外和体内均能显著抑制GBM的生长。DGKα具有广泛的 与细胞代谢的关键介质（包括mTOR、NF-κB和HIF-1α）相互作用。尽管如此， DGKα在GBM代谢调节中的作用尚未研究。根据我们的研究，我们 初步表明，DGKα是脂质代谢途径的重要调节因子， 用利坦色林抑制显著抑制脂质代谢。DGKα通路与糖酵解有关 通过多种途径。我们最近的研究结果支持了这种串扰，表明葡萄糖的抑制 代谢导致DGKα的激活，并且单独抑制DGKα也会驱动代谢开关 糖酵解的增加我们随后发现，利坦色林和氯尼达明的组合， 一种新的临床上可应用的糖酵解抑制剂，对GBM表现出显著的协同作用和细胞毒性。我们 因此，建议开发一种图像引导的治疗方法，以有效地靶向能量代谢， GBM。我们的目的是通过抑制DGKα来诱导代谢成瘾，以增强糖酵解，并确定 使用下一代数字光子计数PET/CT成像系统增加葡萄糖代谢。我们 将随后用氯尼达明靶向糖酵解途径。我们将研究以下目标： 确定DGKα调节脂质代谢的作用，Aim 2将评估代谢向 DGKα抑制后糖酵解增加，并将测试利坦色林和氯尼达明联合治疗的疗效 治疗氯尼达明和利坦色林都是口服生物可利用的，并且已经在临床试验中进行了测试。 并被证明对人体安全。考虑到有利的药理学特征，包括非常好的BBB渗透， 如果成功的话，所提出的联合治疗可以迅速转移到临床，在患有以下疾病的患者中进行试验： GBM和其他癌症。

Project Summary Glioblastoma (GBM) cells reversibly switch their metabolic phenotype to adapt to changes in the microenvironment and sustain their growth. For this reason, targeting a single metabolic pathway is ineffective. One viable approach is to induce a shift towards a specific metabolic phenotype and then target the activated metabolic pathway. With our recent report in Neuro-Oncology, we demonstrated diacylglycerol kinase alpha (DGKα) as a novel therapeutic vulnerability in GBM. We showed that targeting DGKα with the clinically applicable DGKα inhibitor, ritanserin, significantly suppresses GBM growth in vitro and in vivo. DGKα has extensive interactions with the key mediators of cellular metabolism, including mTOR, NF-κB, and HIF-1α. Despite this, the role of DGKα in the regulation of metabolism has not been studied in GBM. Following up on our study, we preliminarily showed that DGKα functions as a crucial regulator of lipid metabolic pathways and that DGKα inhibition with ritanserin significantly suppresses lipid metabolism. The DGKα pathway is connected to glycolysis through multiple pathways. Supporting this crosstalk, our recent findings suggest that suppression of glucose metabolism leads to the activation of DGKα, and also that DGKα inhibition alone drives a metabolic switch towards increased glycolysis. We subsequently showed that the combination of ritanserin and lonidamine, a novel, clinically applicable inhibitor of glycolysis, exhibits significant synergy and cytotoxicity against GBM. We therefore propose to develop an image-guided therapeutic approach to effectively target energy metabolism in GBM. We aim to induce metabolic addiction to enhanced glycolysis through DGKα inhibition and determine the increase in glucose metabolism using a next-generation digital photon counting PET/CT imaging system. We will subsequently target the glycolytic pathway with lonidamine. We will study the following aims: Aim 1 will determine the role of DGKα to regulate lipid metabolism and Aim 2 will evaluate the metabolic switch towards increased glycolysis upon DGKα inhibition and will test the efficacy of the combined ritanserin and lonidamine treatment. Both lonidamine and ritanserin are orally bioavailable and have already been tested in clinical trials and proven safe in humans. Given the favorable pharmacologic features, including very good BBB penetration, if successful, the proposed combined treatment can be quickly transferred to the clinic for trials in patients with GBM and other cancers.