Pharmacological and Chemical Approaches to Repurpose an Antiepileptic for Glioblastoma Treatment

项目概要/摘要 多形性胶质母细胞瘤（GBM）是最具侵袭性的原发性脑肿瘤， 存活率（~5%）。GBM转移到不同的大脑区域， 难尽管进行了放疗和化疗，中位生存时间轴仍为15 个月GBM治疗中的主要挑战包括晚期诊断、转移、耐药性、肿瘤复发、肿瘤转移、肿瘤复发、肿瘤转移。 化疗药物和由于血脑屏障引起的药物递送问题。因此， 开发用于GBM的新药物疗法是非常必要的。癌细胞重新连接 与致癌基因和肿瘤抑制基因密切相关的代谢途径。的 代谢重编程赋予GBM在存活、增殖、转移 耐药性和免疫逃避。此外，最近在癌症代谢领域的研究 揭示了一个重要的“乳酸穿梭”，解释了乳酸转移的关键作用， 进入肿瘤微环境。乳酸盐利用与大脑高度相关 肿瘤如GBM。我们的长期目标是靶向肿瘤代谢 用于癌症治疗为了实现这个目标，我们筛选了一些代谢 GBM细胞中的抑制剂，揭示了FDA批准的抗癫痫药物的有效性 司替戊醇及其推定的靶乳酸脱氢酶。本研究的目的是阐明 GBM细胞中司替戊醇治疗的分子机制和癌症生物学变化， GBM体内模型。此外，我们还将研究新型衍生物的构效关系 从司替戊醇支架中鉴定出开发有效的抑制剂。此外， 将开发司替戊醇和有效的先导化合物，并在肿瘤异种移植模型中进行测试。 U87异种移植物我们的研究将提供新的见解的机制药理学， 司替戊醇，并且可以导致用于GBM治疗的候选治疗剂的开发。

PROJECT SUMMARY / ABSTRACT Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with a dismal 5-year survival rate (~ 5 %). GBM metastasizes to different brain regions which makes surgical resection difficult. Despite radiation therapy and chemotherapy, the median survival timeline is dire at 15 months. The major challenges in GBM therapy include late diagnosis, metastasis, resistance to chemotherapeutics, and drug delivery issues due to blood-brain barrier. Thus, efforts towards developing novel pharmacotherapies for GBM are highly warranted. Cancer cells rewire their metabolic pathways that are intimately linked to oncogenes and tumor suppressor genes. The metabolic reprogramming confers GBM several advantages in survival, proliferation, metastasis, drug resistance, and immune evasion. In addition, recent research in the cancer metabolism field has revealed an important ‘lactate shuttle’ that explains the key role of lactate transfer from systemic circulation into tumor microenvironment. Lactate utilization is highly relevant for brain tumors such as GBM. Our long-term goal is to pharmacologically target tumor metabolic reprogramming for cancer therapy. Towards that goal, we screened a number of metabolic inhibitors in GBM cells that uncovered effectiveness of an FDA-approved antiepileptic drug stiripentol with its putative target lactate dehydrogenase. The objective of this study is to elucidate molecular mechanism and changes in cancer biology by stiripentol treatment in GBM cells and GBM in vivo models. In addition, we will study structure-activity relationships of novel derivatives identified from stiripentol scaffold to develop potent inhibitors. Additionally, formulations of stiripentol and potent lead compounds will be developed and tested in the tumor xenograft model of U87 xenografts. Our research will offer novel insights in the mechanistic pharmacology of stiripentol and can lead to the development of candidate therapeutics for GBM treatment.