Maximizing the efficacy of MDM2 inhibitor therapy for MDM2-amplified glioblastoma

PROJECT DESCRIPTION/ABSTRACT MDM2 amplification occurs in 3.5% of all malignancies and in approximately 10% of several highly aggressive malignancies, including glioblastoma. MDM2 is a critical negative regulator of the tumor suppressor p53, and high-level MDM2 amplification results in functional inactivation of p53 and is a genomic-driver event in tumorigenesis of these tumors. Even in tumors with ‘normal’ MDM2 expression, disruption of the MDM2/p53 pathway can trigger apoptosis. In this context, multiple pharmaceutical companies have developed potent MDM2 inhibitors that are in advanced clinical development for a variety of malignancies. In our studies with a highly potent MDM2 inhibitor from Boehringer Ingelheim (Brigimadlin; BI 907828), we found that MDM2- amplified glioblastoma (GBM) and sarcomas are exquisitely sensitive to this drug. Specific to MDM2-amplified tumors, drug treatment is associated with degradation of the pro-survival MCL1 protein and upregulation of other pro-apoptotic proteins. Moreover, brigimadlin treatment results in suppression of multiple DNA repair pathways that are critical for recovery from both endogenous and exogenous genotoxic stress. Based on these observations, we hypothesize that the combination of enhanced apoptosis and an inability to repair DNA damage creates a unique vulnerability of MDM2-amplified GBM to brigimadlin. We will test this in three Aims: Aim 1: Evaluate mechanism of exquisite MDM2 inhibitor sensitivity in MDM2 amplified GBM Aim 2: Define the effects of brigimadlin on cellular response to genotoxic stress Aim 3: Evaluate strategies to enhance the therapeutic window for MDM2 inhibitors in GBM