UC Irvine

Abstract Recent research has shown a role of proteasome ubiquitination in medulloblastoma tumorigenesis and proteasome inhibition as a possible therapeutic target. In medulloblastoma primary cell culture and in a Patched1 haploinsufficiency medulloblastoma mice model, bortezomib, a proteasome inhibitor, has been shown to limit tumor growth via induction of apoptosis and inhibition of cell proliferation. However, its clinical utility is limited by its inability to cross the blood brain barrier and association with peripheral neuropathy. Marizomib, a more lipophilic proteasome inhibitor, has been shown to cross the blood brain barrier in preclinical studies and is being used in Phase III studies for adult glioblastoma in combination with radiation and temozolomide. Here, we evaluated dose dependent cell killing of marizomib in two group 3, myc-amplified medulloblastoma cell cultures. IC50’s were determined and were consistent with and slightly lower than that seen in adult glioblastoma cell cultures. We suggest marizomib warrants further investigation as a potential therapeutic target for recurrent medulloblastoma. Future studies will include determination of IC50’s for marizomib in cell lines for all medulloblastoma molecular subgroups and primary cell cultures as well as in vitro testing with patient-derived xenograft models.