TY - JOUR
T1 - Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma
AU - Hanaford, Allison R.
AU - Alt, J.
AU - Rais, Rana
AU - Wang, Sabrina Z.
AU - Kaur, Harpreet
AU - Thorek, Daniel L.J.
AU - Eberhart, Charles G.
AU - Slusher, Barbara S.
AU - Martin, Allison M.
AU - Raabe, Eric H.
N1 - Funding Information:
Funding support: NINDS 1R01NS103927 (BSS and EHR); NCI R01 R01CA229451 (BSS), Alex's Lemonade Stand Foundation and the Swifty Foundation (EHR and BSS); Children's Cancer Foundation (EHR and BSS); The Spencer Grace Foundation (EHR), The Ace for a Cure Foundation (EHR); Beez Foundation (AMM); Giant Food Pediatric Cancer Research Fund; National Cancer Institute Core Grant to the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center (P30CA006973).
Publisher Copyright:
© 2019 The Authors
PY - 2019/10
Y1 - 2019/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85069607453&partnerID=8YFLogxK
U2 - 10.1016/j.tranon.2019.05.013
DO - 10.1016/j.tranon.2019.05.013
M3 - Article
C2 - 31340195
AN - SCOPUS:85069607453
SN - 1936-5233
VL - 12
SP - 1314
EP - 1322
JO - Translational Oncology
JF - Translational Oncology
IS - 10
ER -