Phase IIA Trial of Dichloroacetate for Glioblastoma Multiforme, IND137007, 09172019

二氯乙酸治疗多形性胶质母细胞瘤的 IIA 期试验，IND137007，09172019

• 批准号: 10281354
• 负责人: CHETAN BETTEGOWDA
• 金额: $ 54.16万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10281354
• 关键词: Phase; IIA; Trial; Dichloroacetate; Glioblastoma

Abstract: Glioblastoma multiforme (GBM), a grade IV glioma, is the most malignant form of an astrocytoma and is the most common malignant brain tumor in adults. The cause of this primary and highly aggressive cancer is unclear. The current treatment for glioblastoma is limited to maximal safe surgical resection, followed by chemotherapy and radiation therapy. Unfortunately, virtually all patients will have tumor recurrence and die of this disease. While survival without treatment is approximately three months, survival following treatment is only 12 to 15 months. Less than 5% of people survive longer than five years. A cardinal metabolic characteristic of tumorigenesis is a metabolic shift in which glycolysis, even in the presence of adequate tissue oxygen, increases disproportionately relative to oxidative phosphorylation (OXPHOS), a phenomenon known as the Warburg effect. This glycolytic shift occurs in GBM and is mechanistically associated with post-translational inhibition of the mitochondrial pyruvate dehydrogenase complex (PDC), which normally catalyzes the rate-limiting step in the aerobic oxidation of glucose-derived pyruvate and lactate. PDC inhibition is due to transcriptional upregulation of one or more of four pyruvate dehydrogenase kinase isoforms (PDK 1-4) that inhibit PDC by reversible phosphorylation. Dichloroacetate (DCA), the prototypic PDK inhibitor, readily crosses the blood-brain barrier and represents an entirely new class of small molecule metabolic modulators that act in mitochondria to reset cellular homeostasis in various congenital and acquired metabolic disorders. Indeed, pharmacological inhibition of PDK in cancer cells by DCA restores PDC activity, reverses the Warburg effect and induces a caspase-mediated selective apoptosis of tumors. Extensive pre-clinical research and early clinical trials in patients with recurrent GBM and other brain tumors indicate that DCA may be a safe and uniquely effective metabolic therapy for GBM. DCA inhibits its own metabolism and its only clinically limiting toxicity is reversible peripheral neuropathy. To mitigate this adverse effect, we developed and validated a genotyping method for genetics-based dosing of DCA that dichotomizes subjects into fast and slow drug metabolizers, leading to safe, personalized DCA dosing.

抽象的： 胶质母细胞瘤多形（GBM），一种IV级神经胶质瘤，是最恶性的形式 星形胶质细胞瘤是成人最常见的恶性脑肿瘤。这一主要的原因 高度侵略性的癌症尚不清楚。当前的胶质母细胞瘤治疗仅限于 最大的安全手术切除，然后进行化学疗法和放射治疗。很遗憾， 几乎所有患者都会复发并死于这种疾病。而生存没有 治疗大约三个月，治疗后的生存只有12到15个月。 不到5％的人的生存超过五年。 肿瘤发生的基本代谢特征是一种代谢转移，糖酵解糖酵解， 即使存在足够的组织氧，相对于氧化，也会增加不成比例的增加 磷酸化（Oxphos），一种称为沃堡效应的现象。这种糖酵解的转变 发生在GBM中，与翻译后抑制有关 线粒体丙酮酸脱氢酶复合物（PDC），通常催化速率限制 踏上葡萄糖衍生的丙酮酸和乳酸的有氧氧化。 PDC抑制是由于 四个或多个丙酮酸脱氢酶激酶同工型中的一个或多个转录上调（PDK 1-4）通过可逆磷酸化抑制PDC。二氯乙酸（DCA），原型PDK 抑制剂很容易越过血脑屏障，代表了一类全新的小型小 在线粒体中起作用的分子代谢调节剂可重置各种细胞稳态 先天性和获得的代谢疾病。实际上，PDK在癌症中对PDK的抑制作用 DCA细胞恢复PDC活性，逆转Warburg效应并诱导caspase介导 肿瘤的选择性凋亡。大量临床前研究和患者的早期临床试验 复发性GBM和其他脑肿瘤表明DCA可能是安全且独特的 GBM的代谢疗法。 DCA抑制其自身的新陈代谢，其唯一的临床限制毒性是可逆的外围 神经病。为了减轻这种不利影响，我们开发并验证了一种基因分型方法 用于基于遗传学的DCA剂量，将受试者二分化为快速和缓慢的药物 代谢物，导致安全，个性化的DCA给药。