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： 多形性胶质母细胞瘤 (GBM) 是一种 IV 级胶质瘤，是胶质母细胞瘤中最恶性的一种形式 星形细胞瘤是成人最常见的恶性脑肿瘤。造成这个原发性的原因 高度侵袭性癌症尚不清楚。目前胶质母细胞瘤的治疗仅限于 最大程度安全的手术切除，然后进行化疗和放射治疗。很遗憾， 几乎所有患者都会出现肿瘤复发并死于这种疾病。虽然生存没有 治疗时间约为三个月，治疗后生存期仅为12至15个月。 不到 5% 的人存活时间超过五年。 肿瘤发生的一个主要代谢特征是糖酵解、 即使存在足够的组织氧，相对于氧化而言，也会不成比例地增加 磷酸化（OXPHOS），这种现象被称为瓦尔堡效应。这种糖酵解转变 发生在 GBM 中，在机制上与翻译后抑制相关 线粒体丙酮酸脱氢酶复合物（PDC），通常催化限速 葡萄糖衍生的丙酮酸和乳酸的有氧氧化过程中的步骤。 PDC 抑制是由于 四种丙酮酸脱氢酶激酶亚型（PDK）中一种或多种的转录上调 1-4)通过可逆磷酸化抑制PDC。二氯乙酸 (DCA)，原型 PDK 抑制剂，很容易穿过血脑屏障，代表一类全新的小分子 分子代谢调节剂，在线粒体中发挥作用，以重置各种细胞的稳态 先天性和后天性代谢紊乱。事实上，PDK 在癌症中的药理学抑制作用 DCA 恢复 PDC 活性，逆转 Warburg 效应并诱导 caspase 介导的细胞 肿瘤的选择性凋亡。广泛的临床前研究和早期临床试验 复发性 GBM 和其他脑肿瘤的治疗表明 DCA 可能是一种安全且独特有效的方法 GBM 的代谢疗法。 DCA 抑制其自身代谢，其唯一的临床限制性毒性是可逆的外周毒性 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，将受试者分为快速药物和慢速药物 代谢物，从而实现安全、个性化的 DCA 剂量。