MDM2 inhibitors in sarcomas: results and next steps.

Abstract

Purpose of review: Murine double minute 2 (MDM2) is an oncogene that plays a crucial role in regulating the activity of the tumor suppressor protein p53. By binding to p53, MDM2 promotes its degradation, thus promoting the malignant proliferation. The MDM2-p53 interaction has thus generated interest as a therapeutic target, particularly in some sarcomas characterized by the amplification of the MDM2 gene. In this manuscript, we provide an overview of the current and emerging targeted therapies for MDM2-amplified sarcomas.

Recent findings: Although several agents have been developed with promising results in preclinical studies, these molecules have failed to show conclusive benefit in clinical trials. Nevertheless, the MDM2-p53 pathway inhibition remains an area of ongoing investigation, including the development of novel inhibitors and combination strategies.

Summary: In the era of precision medicine, there is an unmet need for new effective therapies in patients with inoperable/metastatic sarcomas. In some histotypes, MDM2 is overexpressed due to gene amplification, leading to a reduced p53 activity and then in oncogenic transformation. By blocking the activity of MDM2, p53 function can be restored, potentially leading to tumor cell death. However, further research is needed to optimize the translation of MDM2 inhibitors into the clinical setting.