JHU395

Based on prior studies showing enhanced efficacy when GA inhibition was combined with the antimetabolite 6-mercaptopurine (6-MP), we hypothesized that such a combination would be efficacious in MPNST. When combined with JHU395, Pro-905 enhanced the colony formation inhibitory potency of JHU395 in human MPNST cells and augmented the antitumor efficacy of JHU395 in mice. In summary, the dual inhibition of the de novo and purine salvage pathways in preclinical models may safely be used to enhance therapeutic efficacy against MPNST.

Treatment of mice bearing orthotopic xenografts of human MYC-amplified medulloblastoma with JHU395 increased median survival from 26 to 45 days compared with vehicle control mice (p < 0.001 by log-rank test). These data provide preclinical justification for the ongoing development and testing of brain-targeted DON prodrugs for use in medulloblastoma.

Twice weekly 15mg/kg dosing of JHU395 significantly extended the survival of the mice with D425 MED orthotopic xenografts (p<0.001 by log-rank test comparing treated vs vehicle control). Glutamine antagonists exploit MYC-amplified medulloblastoma's reliance on glutamine metabolism and may have therapeutic applications in human patients.

Tumor metabolomics studies were performed to investigate metabolic differences between single agent JHU395, Pro-905, and combination treated mice. Protide purine antimetabolites in combination with glutamine antagonists are tolerated and efficacious in Ras-driven sarcoma models in preclinical studies.