Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma

被引：57

作者：

Hanaford, Allison R. ^{[1
]}

Alt, Jesse ^{[2
]}

Rais, Rana ^{[2
,3
]}

Wang, Sabrina Z. ^{[1
]}

Kaur, Harpreet ^{[1
]}

Thorek, Daniel L. J. ^{[4
,5
]}

Eberhart, Charles G. ^{[6
,7
]}

Slusher, Barbara S. ^{[2
,3
]}

Martin, Allison M. ^{[1
,7
]}

Raabe, Eric H. ^{[1
,6
,7
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Div Pediat Oncol, Baltimore, MD USA

[2] Johns Hopkins Univ, Johns Hopkins Drug Discovery, Sch Med, Baltimore, MD USA

[3] Johns Hopkins Univ, Dept Neurol, Sch Med, Baltimore, MD USA

[4] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA

[5] Washington Univ, Dept Biomed Engn, St Louis, MO USA

[6] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA

[7] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Sch Med, Baltimore, MD 21287 USA

来源：

TRANSLATIONAL ONCOLOGY | 2019年 / 12卷 / 10期

关键词：

LONG-TERM SURVIVORS; NEURAL STEM-CELLS; CHILDHOOD-CANCER; AEROBIC GLYCOLYSIS; METABOLISM; 6-DIAZO-5-OXO-L-NORLEUCINE; TUMORS; TRANSFORMATION; ADDICTION; MICE;

D O I：

10.1016/j.tranon.2019.05.013

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

A subset of poor-prognosis medulloblastoma has genomic amplification of MYC. MYC regulates glutamine metabolism in multiple cellular contexts. We modified the glutamine analog 6-diazo-5-oxo-l-norleucine (DON) to mask its carboxylate and amine functionalities, creating a prodrug termed JHU-083 with increased oral bioavailability. We hypothesized that this prodrug would kill MYC-expressing medulloblastoma. JHU-083 treatment caused decreased growth and increased apoptosis in human MYC-expressing medulloblastoma cell lines. We generated a mouse MYC-driven medulloblastoma model by transforming C57BL/6 mouse cerebellar stem and progenitor cells. When implanted into the brains of C57BL/6 mice, these cells formed large cell/anaplastic tumors that resembled aggressive medulloblastoma. A cell line derived from this model was sensitive to JHU-083 in vitro. Oral administration of JHU-038 led to the accumulation of micromolar concentrations of DON in the mouse brain. JHU-083 treatment significantly increased the survival of immune-competent animals bearing orthotopic tumors formed by the mouse cerebellar stem cell model as well as immune-deficient animals bearing orthotopic tumors formed by a human MYC-amplified medulloblastoma cell line. These data provide pre-clinical justification for the ongoing development and testing of orally bioavailable DON prodrugs for use in medulloblastoma patients.

引用

页码：1314 / 1322

页数：9

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