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

Allison R. Hanaford, J. Alt, Rana Rais, Sabrina Z. Wang, Harpreet Kaur, Daniel L.J. Thorek, Charles G. Eberhart, Barbara S. Slusher, Allison M. Martin, Eric H. Raabe

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1314-1322
Number of pages9
JournalTranslational Oncology
Volume12
Issue number10
DOIs
StatePublished - Oct 2019
Externally publishedYes

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Medulloblastoma
Prodrugs
Glutamine
Brain
Growth
Norleucine
Stem Cells
Inbred C57BL Mouse
Cell Line
Diazooxonorleucine
Neoplasms
Masks
Biological Availability
Amines
Oral Administration
Apoptosis
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma. / Hanaford, Allison R.; Alt, J.; Rais, Rana; Wang, Sabrina Z.; Kaur, Harpreet; Thorek, Daniel L.J.; Eberhart, Charles G.; Slusher, Barbara S.; Martin, Allison M.; Raabe, Eric H.

In: Translational Oncology, Vol. 12, No. 10, 10.2019, p. 1314-1322.

Research output: Contribution to journalArticle

Hanaford, AR, Alt, J, Rais, R, Wang, SZ, Kaur, H, Thorek, DLJ, Eberhart, CG, Slusher, BS, Martin, AM & Raabe, EH 2019, 'Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma', Translational Oncology, vol. 12, no. 10, pp. 1314-1322. https://doi.org/10.1016/j.tranon.2019.05.013
Hanaford, Allison R. ; Alt, J. ; Rais, Rana ; Wang, Sabrina Z. ; Kaur, Harpreet ; Thorek, Daniel L.J. ; Eberhart, Charles G. ; Slusher, Barbara S. ; Martin, Allison M. ; Raabe, Eric H. / Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma. In: Translational Oncology. 2019 ; Vol. 12, No. 10. pp. 1314-1322.
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