CBIO-14: TARGETING PROTEASOME ACTIVITY WITH MARIZOMIB AS A THERAPEUTIC PERSPECTIVE FOR GLIOMA PATIENTS

Inhibition of the Ubiquitin-Proteasome pathway offers promise for the treatment of gliomas, but has yet to be tested because the approved drugs in this class don't penetrate the CNS. Marizomib is a novel second-generation proteasome inhibitor, with advantages over bortezomib and carfilzomib including irreversible inhibition of all three enzymatic activities of the proteasome and superior tolerability. While there are some promising data in preclinical models of solid tumors using proteasome inhibitors, only Marizomib has proven active in intracranial GBM xenografts, prompting the initiation of a Phase I trial in GBM in combination with bevacizumab. We aim to identify potential biomarkers predictive of response to Marizomib in GBM patients. Tumor tissues obtained from glioma patients at Toronto Western Hospital and utilized for proteasome activity assay. Glioma Stem Cells (GSC) isolated from freshly resected gliomas and used for in-vitro characterization of Marizomib treatment on GSCs. DNA and RNA were isolated from tumors of the patients (including those participating in the Phase I trial) for mutational analysis and expression of a cancer gene panel. Data shows significant increase in all three proteasome activities, Chymotrypsin-Like, Trypsin-Like and Caspase-Like, in GBM tumors compared to normal brain tissues, suggesting a role for the proteasome in GBM formation. Furthermore, progression of low-grade astrocytoma to GBM is associated with enhanced Chymotrypsin-Like and Trypsin-Like activities, indicating that targeting these subunits could potentially inhibit the progression of gliomas. In vitro analysis using GSC lines indicates that the GSC cells of proneural and mesenchymal origin differ in response to Marizomib, raising the possibility that molecular signatures associated with GBM subtypes could determine the therapeutic response to Marizomib in GBM patients. In conclusion, Marizomib represents as a potential therapeutic agent for GBM. Further investigation is necessary to assess the therapeutic benefits of Marizomib as a single agent or combined with other agents.