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

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 i...

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Autores principales: Hanaford, Allison R., Alt, Jesse, Rais, Rana, Wang, Sabrina Z., Kaur, Harpreet, Thorek, Daniel L.J., Eberhart, Charles G., Slusher, Barbara S., Martin, Allison M., Raabe, Eric H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Neoplasia Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657308/
https://www.ncbi.nlm.nih.gov/pubmed/31340195
http://dx.doi.org/10.1016/j.tranon.2019.05.013
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author Hanaford, Allison R.
Alt, Jesse
Rais, Rana
Wang, Sabrina Z.
Kaur, Harpreet
Thorek, Daniel L.J.
Eberhart, Charles G.
Slusher, Barbara S.
Martin, Allison M.
Raabe, Eric H.
author_facet Hanaford, Allison R.
Alt, Jesse
Rais, Rana
Wang, Sabrina Z.
Kaur, Harpreet
Thorek, Daniel L.J.
Eberhart, Charles G.
Slusher, Barbara S.
Martin, Allison M.
Raabe, Eric H.
author_sort Hanaford, Allison R.
collection PubMed
description 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.
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spelling pubmed-66573082019-07-31 Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma()() Hanaford, Allison R. Alt, Jesse Rais, Rana Wang, Sabrina Z. Kaur, Harpreet Thorek, Daniel L.J. Eberhart, Charles G. Slusher, Barbara S. Martin, Allison M. Raabe, Eric H. Transl Oncol Original article 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. Neoplasia Press 2019-07-21 /pmc/articles/PMC6657308/ /pubmed/31340195 http://dx.doi.org/10.1016/j.tranon.2019.05.013 Text en © 2019 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original article
Hanaford, Allison R.
Alt, Jesse
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()()
title Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma()()
title_full Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma()()
title_fullStr Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma()()
title_full_unstemmed Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma()()
title_short Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma()()
title_sort orally bioavailable glutamine antagonist prodrug jhu-083 penetrates mouse brain and suppresses the growth of myc-driven medulloblastoma()()
topic Original article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657308/
https://www.ncbi.nlm.nih.gov/pubmed/31340195
http://dx.doi.org/10.1016/j.tranon.2019.05.013
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