Efficacy of MLN4924 (Pevonedistat) for Treatment of GBM
Glioblastoma multiforme (GBM) is the most common malignant brain tumor with a poor survival rate and prognosis. Survival time averages 12-18 months, with only 25% of patients surviving more than a year. Although there have been several clinical trials testing new treatment options, the standard care of surgical resection followed by radiation and/or chemotherapy (temozolomide) has not changed for decades and remains stagnant. The process of protein neddylation is overactivated in GBM, leading to the progression of malignant solid tumors such as GBM. Neddylation is a post-translational modification process that marks proteins for degradation through activity of nNEDD8-activating enzyme (NAE). This led to the development of the NAE inhibitor, MLN4924 (Pevonedistat). MLN4924 has been shown to suppress tumor growth in numerous cancer models by binding to NEDD8 and stabilizing pro-apoptotic factors. Survival data in orthotopic studies of mice show that the patient-derived xenograft line GBM 116 is sensitive to MLN4924, while GBM 102 is not. In this study, immunohistochemistry (IHC) is conducted on brain tissue of mice implanted with GBM116 and GBM102 and treated with MLN4924. The antibody that binds to the MLN4924-NEDD8 adduct confirms that the adduct was created and that Pevonedistat reached its target. In addition, sensitivity of IHC staining will be analyzed and compared with results found in the mouse study. The results from this project can help determine if targeting the neddylation pathway using MLN4924 is a promising treatment option for selected GBM patients.
