Novel brain penetrant metabolic inhibitors to treat MYC-driven medulloblastoma

新型脑渗透性代谢抑制剂可治疗 MYC 驱动的髓母细胞瘤

• 批准号: 9751990
• 负责人: Eric Hutton Raabe
• 金额: $ 38.44万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751990
• 关键词: 10 year old; Acute; Animal Model; Behavior assessment; Biological Assay; Brain; Brain Neoplasms; Brain Pathology; Cell model; Cells; Chemistry; Child; Cleaved cell; Clinical Trials; Development; Dose; Drug Kinetics; Esters; Exhibits; Family suidae; Glutamine; Goals; Grant; Growth; Human; In Vitro; Intestinal permeability; Lead; Liver; MYC gene; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Metabolic; Metabolism; Methods; Modeling; Mus; Norleucine; Oral Administration; Oxidation-Reduction; Patients; Pediatric Neoplasm; Penetration; Peripheral; Plasma; Primates; Prodrugs; Proto-Oncogenes; Radiation; Research Project Grants; SLC2A1 gene; Survival Rate; System; Testing; Therapeutic Index; Toxic effect; Work; Xenograft Model; Xenograft procedure; base; candidate selection; chemical stability; chemotherapy; design; drug discovery; early detection biomarkers; experimental study; gastrointestinal; gastrointestinal system; improved; in vivo; inhibitor/antagonist; insight; lipophilicity; liquid chromatography mass spectrometry; medulloblastoma; metabolomics; mouse model; nerve stem cell; novel; patient subsets; scale up; side effect; sodium-dependent vitamin C transporter 2; standard of care; synergism; targeted treatment; therapeutic target; tumor; uptake

PROJECT SUMMARY Medulloblastoma is the most common malignant brain tumor in children. Current treatment includes radiation and multiple chemotherapies which cause severe acute and significant long term side effects. Despite this aggressive treatment, a subset of patients called “Group 3 MYC-amplified medulloblastoma” have a survival rate less than 25%. We and others have shown that MYC-amplified cancers change their energy metabolic requirements and become “glutamine addicted” for their growth and survival. We have developed syngeneic human neural stem cell models which are +/- MYC. Recently we found that the MYC-amplified cells are exquisitely sensitive to the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON), while equally aggressive cells without MYC expression as well normal human neural stem cells are unaffected. While promising, DON is not clinically available. Its development was halted due to gastrointestinal (GI) toxicities, as the GI system is highly dependent on glutamine utilization. Moreover, DON's brain penetration is limited. To overcome DON's peripheral toxicities and to enhance its delivery to brain tumors, we created unique DON prodrugs. They were designed to circulate intact as inert prodrugs in plasma, but permeate and be cleaved to release DON once inside the brain. Compared to equimolar doses of DON, when our lead prodrug JHU-333 was evaluated in vivo (mice, swine, and primates) it resulted in significantly less DON exposure in plasma, and was preferentially biotransformed to DON in the brain, providing a 7-10-fold improvement in the brain/plasma ratio with substantially less GI toxicity. When tested in our MYC-amplified Group 3 orthotopic xenograft model, our brain-penetrable DON prodrug significantly increased survival following oral administration without overt toxicity. Although promising, JHU-333 is not ideal for translational as it exhibits high clearance with a short t1/2 (0.5-2hr). Thus, our main drug discovery focus will be to create metabolically stable DON prodrugs that permeate and are retained in the brain so that their target inhibition can be sustained. In this grant, two PIs with complimentary expertise will design novel DON prodrugs with optimized pharmacokinetic parameters and characterize their efficacy/toxicity profiles in Group 3 MYC-amplified medulloblastoma mouse models. At the completion of these studies we will have developed novel, robust, brian penetrant, and safe inhibitors of glutamine metabolism, laying the ground-work for their rapid introduction into clinical trials.

项目概要 髓母细胞瘤是儿童最常见的恶性脑肿瘤。目前的治疗包括放射治疗 以及导致严重急性和显着长期副作用的多种化疗。尽管如此 积极治疗，称为“第 3 组 MYC 扩增髓母细胞瘤”的患者子集具有生存率 低于25%。我们和其他人已经证明，MYC 扩增的癌症会改变其能量代谢 的需求，并对其生长和生存产生“谷氨酰胺成瘾”。我们开发了同基因 人类神经干细胞模型+/- MYC。最近我们发现MYC扩增的细胞 对谷氨酰胺拮抗剂 6-重氮-5-氧代-L-正亮氨酸 (DON) 极其敏感，同时具有同样的攻击性 没有 MYC 表达的细胞以及正常的人类神经干细胞不受影响。尽管 DON 充满希望，但 临床上不可用。由于胃肠道（GI）毒性，其开发被停止，因为胃肠道系统 高度依赖于谷氨酰胺的利用。而且，DON的大脑渗透力有限。克服呕吐毒素 外周毒性并增强其对脑肿瘤的输送，我们创造了独特的 DON 前药。他们是 设计为在血浆中作为惰性前药完整循环，但一旦渗透并被裂解释放 DON 大脑内部。当我们的先导前药 JHU-333 进行体内评估时，与等摩尔剂量的 DON 相比 （小鼠、猪和灵长类动物）它导致血浆中 DON 暴露显着减少，并且优先 在大脑中生物转化为 DON，使大脑/血浆比率提高 7-10 倍 胃肠道毒性较小。当在我们的 MYC 扩增第 3 组原位异种移植模型中进行测试时，我们的大脑可穿透 DON 前药口服给药后可显着提高存活率，且无明显毒性。虽然 尽管 JHU-333 有希望，但它并不适合转化，因为它具有高清除率和短 t1/2（0.5-2 小时）。因此，我们的 主要药物发现重点将是创造代谢稳定的 DON 前药，使其渗透并保留 以便他们的目标抑制能够持续。在这笔资助中，两名具有互补专业知识的 PI 将设计具有优化药代动力学参数的新型 DON 前药，并表征其 第 3 组 MYC 扩增的髓母细胞瘤小鼠模型中的功效/毒性特征。完成这些工作后 通过研究，我们将开发出新型、强健、具有渗透性且安全的谷氨酰胺代谢抑制剂，奠定了 为其快速引入临床试验奠定了基础。