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: 10586015
• 负责人: Inan Olmez
• 金额: $ 20.3万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586015
• 关键词: Biological Availability; 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; Glycolysis Inhibition; Growth; Heterogeneity; Human; Imaging Device; In Vitro; Lipids; Lonidamine; Malignant Neoplasms; Mediating; Mediator; Metabolic; Metabolic Pathway; Metabolism; Molecular; Morbidity - disease rate; Mus; Oral; Outcome; PET/CT scan; Pathway interactions; Patients; 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; blood-brain barrier penetration; cancer cell; clinical application; combinatorial; cytotoxicity; digital; efficacy evaluation; efficacy testing; experience; gain of function; 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; pharmacologic; 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.

项目摘要 胶质母细胞瘤（GBM）细胞可逆性切换其代谢表型，以适应变化 由于这个原因，微环境和维持其增长。 一种可行的方法是诱导the the tos tos to to to to to to to to the特定的代谢表型和激活 代谢途径。 （DGKα）作为GBM中的无新型治疗脆弱性。 DGKα抑制剂RITANSERIN在体外和体内显着抑制GBM的生长 与细胞代谢的介体相互作用，包括MTOR，NF-κB和HIF-1α。 DGKα在代谢调节中的作用尚未在GBM中研究。 初步表明，DGKα充当脂质代谢的关键调节剂和DGKα 利坦林抑制作用可显着抑制脂质代谢。 通过多个途径。 代谢会导致DGKα的激活，并且仅DGKα抑制作用驱动amttatebolic开关 为了增加糖酵解。 新颖的，适用于糖酵解的临床抑制剂，对GBM表现出明显的协同作用和细胞毒性 因此，建议开发出图像式的疗法以有效靶向能量代谢 GBM。 使用下一代数字光子计数PET/CT成像系统增加葡萄糖代谢 随后将用隆尼丁靶向糖酵解途径。 确定DGKα在调节脂质代谢方面的作用，AIM 2将评估代谢开关TOWITCH DGKα抑制作用增加糖酵解，并将测试合并利坦氏素和隆替胺的功效 治疗。 并在人类中被证明是安全的。 如果取得成功，则可以将提议的合并治疗迅速转移到诊所，以进行试验 GBM和其他癌症。