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

开发图像引导治疗策略以有效靶向胶质母细胞瘤的代谢重编程

• 批准号: 10288876
• 负责人: Inan Olmez
• 金额: $ 24.35万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288876
• 关键词: Caring; Cells; Citric Acid Cycle; Clinic; Clinical Trials; Combined Modality Therapy; Diacylglycerol Kinase; Diglycerides; Drug toxicity; Energy Metabolism; Enzymes; Exhibits; Exploratory/Developmental Grant; FRAP1 gene; Genetic; Genus Hippocampus; Glioblastoma; Glycolysis; Growth; Heterogeneity; Human; Imaging Device; In Vitro; Lipids; Lonidamine; Malignant Neoplasms; Mediating; Mediator of activation protein; Metabolic; Metabolic Pathway; Metabolism; Molecular; Morbidity - disease rate; Mus; Oral; Outcome; PET/CT scan; Pathway interactions; Patients; Pharmacology; Phenotype; Phosphatidic Acid; Phosphotransferases; Photons; Primary Brain Neoplasms; Prognosis; Regulation; Reporting; Research; Risk; Ritanserin; Role; Second Messenger Systems; Stress; Testing; Therapeutic; Therapeutic Agents; Tumor Volume; Xenograft Model; addiction; base; blood-brain barrier penetration; cancer cell; clinical application; combinatorial; cytotoxicity; digital; efficacy evaluation; efficacy testing; experience; glucose metabolism; glucose monitor; glucose uptake; hexokinase; image guided; imaging system; improved; in vivo; inhibitor; lipid metabolism; lipidomics; loss of function; metabolic phenotype; metabolome; neuro-oncology; next generation; novel; novel therapeutic intervention; novel therapeutics; small molecule inhibitor; synergism; therapeutic target

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.

项目概要 胶质母细胞瘤（GBM）细胞可逆地转换其代谢表型以适应环境的变化 因此，针对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，然后针对激活的 通过我们最近在神经肿瘤学上的报告，我们证明了二酰甘油激酶α。 （DGKα）作为 GBM 的一种新的治疗脆弱性，我们表明靶向 DGKα 具有临床适用性。 DGKα 抑制剂利坦色林 (ritanserin) 在体外和体内均能显着抑制 GBM 生长。 与细胞代谢的关键介质（包括 mTOR、NF-κB 和 HIF-1α）的相互作用。 DGKα 在 GBM 代谢调节中的作用尚未在我们的研究中得到研究。 初步表明 DGKα 作为脂质代谢途径的关键调节因子发挥作用，并且 DGKα 利坦色林 (ritanserin) 的抑制可显着抑制脂质代谢。 DGKα 途径与糖酵解有关。 我们最近的研究结果表明，通过多种途径来支持这种串扰。 代谢导致 DGKα 的激活，并且仅抑制 DGKα 即可驱动代谢开关 我们随后证明利坦舍林和氯尼达明的组合可以增加糖酵解。 新型临床适用的糖酵解抑制剂，对 GBM 表现出显着的协同作用和细胞毒性。 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 我们的目标是通过 DGKα 抑制诱导对增强糖酵解的代谢成瘾，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。 随后将用氯尼达明靶向糖酵解途径。我们将研究以下目标：目标 1 将。 确定 DGKα 调节脂质代谢的作用，目标 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用药的功效 氯尼达明和利坦色林均可口服生物利用，并已在临床试验中进行了测试。 并被证明对人类是安全的，因为具有良好的药理学特性，包括非常好的 BBB 渗透性， 如果成功，所提出的联合治疗可以迅速转移到诊所，在患有以下疾病的患者中进行试验 GBM 和其他癌症。