Abstract
Glioblastoma (GBM) is the most prevalent and aggressive malignant tumor of the central nervous system in adults. Patients with GBM have a poor prognosis, with a median survival of 15 months with current standard-of-care treatment, consisting of surgery followed by radiotherapy with concomitant and adjuvant temozolomide. Marizomib is an irreversible, pan-proteasome inhibitor that crosses the blood–brain barrier, currently under investigation in a phase 3 trial for newly diagnosed GBM. This preclinical study investigated the mechanism of action of marizomib in patient-derived GBM spheres and explored a series of combination treatments to further enhance its antitumor potency. Marizomib inhibited the 3 proteolytic subunits of the 20S proteasome in a dose-dependent manner, and this correlated with reduced cell proliferation compared with vehicle control (dimethyl sulfoxide). Marizomib induced transient expression of unfolded protein response (UPR) pathway genes, with a sustained upregulation of the SQSTMI gene. Combining marizomib with the histone deacetylase (HDAC) inhibitors panobinostat and vorinostat demonstrated cooperative upregulation of UPR genes and enhanced inhibition of cell proliferation. Furthermore, marizomib treatment upregulated survivin, an inhibitor of apoptosis protein (IAP). Compared with marizomib alone, addition of the IAP inhibitors AZD5582 and LCL161 increased marizomib antiproliferative activity in GBM spheres. In conclusion, these findings indicate that combining marizomib with HDAC or IAP inhibitors can enhance the overall antitumor activity of marizomib in patient-derived GBM spheres. Additional studies in preclinical models of GBM are needed to corroborate these findings.