MDB-03. DFMO AS A TREATMENT STRATEGY IN GROUP 3 MEDULLOBLASTOMA

Abstract Medulloblastomas, the most common malignant brain tumor in children, are subdivided into 4 major molecular subgroups. Among these, Group 3 medulloblastomas have one of the worst prognoses. We have recently identified the LIN28B pathway as being critically important in Group 3 medulloblastoma growth in vitro and in vivo. There are few targeted inhibitors of the LIN28B pathway and none are currently in clinical practice. Recently DFMO has been identified as an indirect inhibitor of the LIN28B-let-7 axis through its inhibition of polyamine biosynthesis. Another recent study identified ornithine, a precursor to polyamines, as being upregulated in MYC amplified Group 3 medulloblastoma. Importantly, DFMO has been demonstrated to achieve high concentrations in brain tumors in a rat glioma model with minimal systemic toxicity. Based on this we hypothesize that DFMO would be attractive agent for Group 3 medulloblastoma treatment as it would inhibit both polyamine synthesis and LIN28B and potentially achieve high tumor concentrations. Here we demonstrate that treatment with increasing concentration of DFMO leads to significant reduction in Group 3 medulloblastoma viability, increased apoptosis and reduced levels of LIN28B and its downstream targets. We are currently investigating whether this drug can effectively inhibit in vivo tumor growth in orthotopic xenograft models of Group 3 medulloblastoma.