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

基本信息

批准号：
10238803
负责人：
Eric Hutton Raabe
金额：
$ 45.66万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10238803
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 aggressive therapy base candidate selection chemical stability chemotherapy design drug discovery early detection biomarkers early phase clinical trial efficacy evaluation 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 derived xenograft model patient subsets scale up side effect sodium-dependent vitamin C transporter 2 standard of care stem cell model synergism targeted treatment therapeutic target tumor uptake

项目摘要

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，目前的治疗方法包括放射治疗。尽管如此，多种化疗仍会导致严重的急性和显着的长期副作用。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我们和其他人已经证明，MYC 扩增的癌症会改变其能量代谢。为了它们的生长和生存而变得“谷氨酰胺成瘾”。 +/- MYC 的人类神经干细胞模型最近我们发现 MYC 扩增的细胞是对谷氨酰胺拮抗剂 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，但 DON 却有希望。由于胃肠道（GI）毒性，其开发已停止，因为胃肠道系统尚未上市。高度依赖谷氨酰胺的利用，而且，DON 的大脑渗透性也受到限制。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。设计用于在血浆中作为惰性前药完整消除，但一旦渗透并被裂解释放 DON 当我们的主要前药 JHU-333 在体内进行评估时，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。有前景的是，JHU-333 并不适合转化，因为它具有高清除率和短 t1/2（0.5-2 小时）。主要药物发现重点将是创造代谢稳定的 DON 前药，使其渗透并保留在这项资助中，两名具有互补专业知识的 PI 能够在大脑中维持其目标抑制。将设计具有优化药代动力学参数的新型 DON 前药并表征其完成这些研究后，第 3 组 MYC 扩增的髓母细胞瘤小鼠模型的功效/毒性特征。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，奠定了基础为其快速引入临床试验奠定了基础。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Discovery of tert-Butyl Ester Based 6-Diazo-5-oxo-l-norleucine Prodrugs for Enhanced Metabolic Stability and Tumor Delivery.

DOI：
10.1021/acs.jmedchem.3c01681
发表时间：
2023-11-23
期刊：
JOURNAL OF MEDICINAL CHEMISTRY
影响因子：
7.3
作者：
Novotna, Katerina;Tenora, Lukas;Prchalova, Eva;Paule, James;Alt, Jesse;Veeravalli, Vijay;Lam, Jenny;Wu, Ying;Snajdr, Ivan;Gori, Sadakatali;Mettu, Vijaya Saradhi;Tsukamoto, Takashi;Majer, Pavel;Slusher, Barbara S.;Rais, Rana
通讯作者：
Rais, Rana

Clinical development of metabolic inhibitors for oncology.

DOI：
10.1172/jci148550
发表时间：
2022-01-04
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
Lemberg KM;Gori SS;Tsukamoto T;Rais R;Slusher BS
通讯作者：
Slusher BS

Glutamine Antagonist JHU-083 Normalizes Aberrant Hippocampal Glutaminase Activity and Improves Cognition in APOE4 Mice.

DOI：
10.3233/jad-190588
发表时间：
2020
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
0
作者：
Hollinger KR;Zhu X;Khoury ES;Thomas AG;Liaw K;Tallon C;Wu Y;Prchalova E;Kamiya A;Rojas C;Kannan S;Slusher BS
通讯作者：
Slusher BS

The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling.