Novel brain penetrant metabolic inhibitors to treat MYC-driven medulloblastoma

项目摘要 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 以及引起严重急性和显著长期副作用的多种化疗。尽管如此 积极的治疗，一个被称为“第3组MYC扩增的髓母细胞瘤”的患者亚组的生存率 低于25%。我们和其他人已经证明，MYC扩增的癌症改变了它们的能量代谢， 需要和成为“谷氨酰胺成瘾”为他们的成长和生存。我们开发了同基因的 人神经干细胞模型是+/- 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）非常敏感， 没有MYC表达的细胞以及正常人神经干细胞不受影响。虽然承诺，唐是 临床上不可用。由于胃肠道（GI）毒性，其发展停止，因为GI系统是 高度依赖谷氨酰胺利用。此外，DON的大脑渗透是有限的。为了克服唐 为了降低外周毒性并增强其向脑肿瘤的递送，我们创造了独特的DON前药。他们 被设计为在血浆中作为惰性前药完整地循环，但渗透并被切割以释放DON一次 大脑内部与等摩尔剂量的DON相比，当我们的先导前药JHU-333在体内进行评价时， (mice，猪和灵长类动物），它导致血浆中DON暴露显著减少，并且优先被 在脑中生物转化为DON，使脑/血浆比率提高7-10倍， 胃肠道毒性更小。当在我们的MYC扩增的第3组原位异种移植模型中进行测试时，我们的脑可穿透性 DON前药在口服给药后显著增加存活率，而无明显毒性。虽然 JHU-333是一种很有前途的药物，但对于翻译来说并不理想，因为它表现出高清除率和短的t1/2（0.5- 2 hr）。所以我们 主要的药物发现重点将是创造代谢稳定的DON前药， 这样他们的目标抑制才能持续。在这项拨款中，两名具有免费专业知识的PI 将设计具有优化的药代动力学参数的新型DON前药，并表征其 在第3组MYC扩增的髓母细胞瘤小鼠模型中的疗效/毒性特征。在完成这些 研究，我们将开发新的，强大的，布赖恩渗透，和安全的谷氨酰胺代谢抑制剂，奠定 为它们迅速进入临床试验奠定了基础。

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.