Details

Autor(en) / Beteiligte

• 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.

Titel

Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma12

Ist Teil von

• Translational oncology, 2019-07, Vol.12 (10), p.1314-1322

Ort / Verlag

Neoplasia Press

Erscheinungsjahr

2019

Link zum Volltext

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• 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.