MDM2 Inhibition in the Treatment of Glioblastoma: From Concept to Clinical Investigation

Abstract

Inhibition of the interaction between MDM2 and p53 has emerged as a promising strategy for combating cancer, including the treatment of glioblastoma (GBM). Numerous MDM2 inhibitors have been developed and are currently undergoing rigorous testing for their potential in GBM therapy. Encouraging results from studies conducted in cell culture and animal models suggest that MDM2 inhibitors could effectively treat a specific subset of GBM patients with wild-type TP53 or functional p53. Combination therapy with clinically established treatment modalities such as radiation and chemotherapy offers the potential to achieve a more profound therapeutic response. Furthermore, an increasing array of other molecularly targeted therapies are being explored in combination with MDM2 inhibitors to increase the effects of individual treatments. While some MDM2 inhibitors have progressed to early phase clinical trials in GBM, their efficacy, alone and in combination, is yet to be confirmed. In this article, we present an overview of MDM2 inhibitors currently under preclinical and clinical investigation, with a specific focus on the drugs being assessed in ongoing clinical trials for GBM patients.

Keywords: ALRN-6924; BI-907828; MDM2; clinical trial; glioblastoma; idasanutlin; navtemadlin; p53; small molecule; targeted therapy.

Figure 1

Summary of the p53–MDM2 regulatory loop and its intracellular implications. (1) MDM2 prevents p53 from regulating the transcription of MDM2 and other downstream target genes by binding to p53 directly. (2) Through interaction with various cytoplasmic proteins, MDM2 promotes SUMOylation and nuclear export of p53. (3) Most notably, MDM2 is an E3 ubiquitin ligase that targets p53 via ubiquitination for proteasomal degradation and thereby suppresses p53 transcriptional activity. All of these mechanisms work together to reduce p53 activity in the absence of cellular stress. Created with BioRender.com (accessed on 15 February 2023).

Figure 2

Potential synergistic interactions between different therapeutic modalities and MDM2 inhibitors. Chemotherapy and radiation therapy (RT) remain the most promising and thoroughly researched combination partners for MDM2 inhibition. MDM2 and p53 activities are closely associated with the efficacy of chemotherapeutic drugs that work by damaging DNA, and inhibition of MDM2 renders tumor cells more susceptible to these types of pharmacotherapies. MDM2 inhibitors increase the effectiveness of RT by radiosensitizing tumor cells. Additionally, potential synergistic pathway inhibition with small-molecule-targeted therapies and other treatment modalities, such as immunotherapy, is conceivable and the subject of ongoing research (colored arrowheads signify examples of targeted molecules). Created with BioRender.com (accessed on 15 February 2023).