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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.

项目总结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重大长期副作用的多种化疗。尽管如此积极治疗，一组被称为“第3组MYC扩增髓母细胞瘤”的患者存活率高不到25%。我们和其他人已经证明，MYC扩增的癌症会改变他们的能量代谢并成为“谷氨酰胺成瘾”的生长和生存。我们已经开发出了同基因人神经干细胞模型为+/-MYC。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去亮氨酸(DON)非常敏感，同时同样具有攻击性没有MYC表达的细胞以及正常的人类神经干细胞不受影响。虽然很有希望，但唐是在临床上不可用。它的开发由于胃肠道(GI)毒性而停止，就像GI系统一样高度依赖谷氨酰胺的利用。此外，唐的大脑渗透率是有限的。为了克服唐的外周毒性和增强其对脑肿瘤的传递，我们创造了独特的DON前药。它们是设计为作为惰性前体药物在血浆中原封不动地循环，但渗透并被切割释放一次DON 在大脑内部。与等摩尔剂量的DON相比，当我们的先导药物JHU-333在体内进行评估时 (小鼠、猪和灵长类动物)它显著减少了血浆中DON的暴露，并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扩增的Group 3原位异种移植模型中进行测试时，我们的大脑穿透性 DON前药可显著提高口服给药后的存活率，且无明显毒性。虽然前景看好，JHU-333不是平移的理想选择，因为它具有短T1/2(0.5-2小时)的高清晰度。因此，我们的主要的药物发现重点将是创造新陈代谢稳定、渗透并保留的DON前药这样他们的目标抑制才能持续下去。在这笔赠款中，两名具有免费专业知识的私人助理将设计具有优化的药代动力学参数的新型DON前药并对其进行表征第3组MYC扩增髓母细胞瘤小鼠模型的疗效/毒性分析。在完成这些操作后我们将开发出新型的、强健的、可穿透大脑的、安全的谷氨酰胺代谢抑制剂。为它们迅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.