Proteasome Inhibitors against Glioblastoma-Overview of Molecular Mechanisms of Cytotoxicity, Progress in Clinical Trials, and Perspective for Use in Personalized Medicine.

ABSTRACT

Proteasome inhibitors are moieties targeting the proteolytic activity of a proteasome, with demonstrated efficacy in certain hematological malignancies and candidate drugs in other types of cancer, including glioblastoma (GBM). They disturb the levels of proteasome-regulated proteins and lead to the cell cycle inhibition and apoptosis of GBM cells. The accumulation of cell cycle inhibitors p21 and p27, and decreased levels of prosurvival molecules NFKB, survivin, and MGMT, underlie proteasome inhibitors' cytotoxicity when used alone or in combination with the anti-GBM cytostatic drug temozolomide (TMZ). The evidence gathered in preclinical studies substantiated the design of clinical trials that employed the two most promising proteasome inhibitors, bortezomib and marizomib. The drug safety profile, maximum tolerated dose, and interaction with other drugs were initially evaluated, mainly in recurrent GBM patients. A phase III study on newly diagnosed GBM patients who received marizomib as an adjuvant to the Stupp protocol was designed and completed in 2021, with the Stupp protocol receiving patients as a parallel control arm. The data from this phase III study indicate that marizomib does not improve the PFS and OS of GBM patients; however, further analysis of the genetic and epigenetic background of each patient tumor may shed some light on the sensitivity of individual patients to proteasome inhibition. The mutational and epigenetic makeup of GBM cells, like genetic alterations to TP53 and PTEN, or MGMT promoter methylation levels may actually determine the response to proteasome inhibition.