Pharmacological and Chemical Approaches to Repurpose an Antiepileptic for Glioblastoma Treatment

项目摘要/摘要 摘要多形性胶质母细胞瘤(GBM)是最具侵袭性的原发脑瘤，其发病时间长达5年之久。 存活率(~5%)。基底膜转移到不同的脑区，需要手术切除 很难。尽管接受了放射治疗和化疗，但15岁的中位生存时间线是可怕的 月份。GBM治疗的主要挑战包括延迟诊断、转移、耐药 化疗药物，以及血脑屏障导致的药物输送问题。因此，努力实现 开发新的治疗基底膜的药物疗法是非常必要的。癌细胞重新连接它们的 与癌基因和肿瘤抑制基因密切相关的代谢途径。这个 代谢重新编程使GBM在存活、增殖、转移、 抗药性和免疫逃避。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”，它解释了乳酸从 体循环进入肿瘤微环境。乳酸利用与大脑高度相关 肿瘤，如基底膜。我们的长期目标是以肿瘤代谢为药理靶点 为癌症治疗重新编程。为了实现这一目标，我们筛选出了一些新陈代谢 发现FDA批准的抗癫痫药物有效性的GBM细胞中的抑制剂 己二醇酯及其可能的靶标乳酸脱氢酶。这项研究的目的是阐明 己三醇作用于GBM细胞的分子机制及肿瘤生物学改变 GBM活体动物模型。此外，我们还将研究新型衍生物的构效关系。 从二苯乙烯醇类支架中鉴定出可开发出有效的抑制剂。此外，该药的配方 将在肿瘤异种移植模型中开发和测试司替普妥和有效的先导化合物。 U87异种移植物。我们的研究将为黄连的机制药理学提供新的见解 并可导致开发治疗基底膜的候选疗法。

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.