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.

The MDM2–p53 Axis Represents a Therapeutic Vulnerability Unique to Glioma Stem Cells

“…In the meantime, our current results suggest that, in order to fully appreciate their therapeutic potential, MDM2 inhibitors may need to be used in the treatment of glioblastoma patients with a minimal residual tumor burden, whose survival is most likely to be dependent on tumor recurrence initiated by glioma stem cells instead of on the growth of residual tumors driven by the proliferation of non-stem tumor cells. Several clinical trials are underway to evaluate MDM2 inhibitors in patients with glioblastoma [53]. Although the actual sensitivity of stem and non-stem tumor cells to MDM2 inhibitors in patients' tumors also remains to be investigated, possible differential sensitivity needs to be considered when interpreting the findings of ongoing trials or designing new trials.…”

Glioblastoma Therapy: Past, Present and Future

“…Furthermore, there is a high occurrence of TP53 and ARF co-inactivation observed in GB [ 480 ]. p53 mutations play a particularly significant role in the development of secondary GBs [ 470 ], and the insurgence/progression of GB, as well as the related chemoresistance, have often been attributed to MDM2 overexpression [ 481 , 482 ].…”

“…One option is to inhibit the MDM2/p53 complex to prevent degradation of the p53, thus restoring the function of wild-type p53 in tumors with mutant p53, and inhibiting gain-of-function mutations in mutant p53 [ 474 , 478 ]. Combining an MDM2 inhibitor with chemotherapy or radiotherapy, higher levels of p53 can be achieved, leading to the activation of apoptosis [ 482 ], which is also a viable strategy to overcome resistance to therapy [ 483 , 484 ]. AMG232 (a p53-MDM2 inhibitor) exhibited the most remarkable efficacy against GB stem cells and spheroids [ 479 , 485 ].…”

“…In a xenograft model of intracranial GB, TMZ/nutlin3a treatment resulted in a significant increase in survival compared with single-agent therapy [ 483 ]. Nutilin-3 was followed by the development of other MDM2 inhibitors such as idasanutlin (RG7388, NCT03158389), AMG232 (NCT01723020), navtemadlin (NCT03107780) and BI-907828 (NCT05376800), which are undergoing clinical trials for GB and other brain cancers [ 482 ].…”