MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer

Abstract

The two murine double minute (MDM) family members MDM2 and MDMX are at the center of an intense clinical assessment as molecular target for the management of cancer. Indeed, the two proteins act as regulators of P53, a well-known key controller of the cell cycle regulation and cell proliferation that, when altered, plays a direct role on cancer development and progression. Several evidence demonstrated that functional aberrations of P53 in tumors are in most cases the consequence of alterations on the MDM2 and MDMX regulatory proteins, in particular in patients with hematological malignancies where TP53 shows a relatively low frequency of mutation while MDM2 and MDMX are frequently found amplified/overexpressed. The pharmacological targeting of these two P53-regulators in order to restore or increase P53 expression and activity represents therefore a strategy for cancer therapy. From the discovery of the Nutlins in 2004, several compounds have been developed and reported with the ability of targeting the P53-MDM2/X axis by inhibiting MDM2 and/or MDMX. From natural compounds up to small molecules and stapled peptides, these MDM2/X pharmacological inhibitors have been extensively studied, revealing different biological features and different rate of efficacy when tested in in vitro and in vivo experimental tumor models. The data/evidence coming from the preclinical experimentation have allowed the identification of the most promising molecules and the setting of clinical studies for their evaluation as monotherapy or in therapeutic combination with conventional chemotherapy or with innovative therapeutic protocols in different tumor settings. Preliminary results have been recently published reporting data about safety, tolerability, potential side effects, and efficacy of such therapeutic approaches. In this light, the aim of this review is to give an updated overview about the state of the art of the clinical evaluation of MDM2/X inhibitor compounds with a special attention to hematological malignancies and to the potential for the management of pediatric cancers.

Keywords: Clinical studies; Leukemia; MDM2; MDMX; Pediatric tumors; Pharmacological inhibitor.

Fig. 1

Expression levels of MDM2 and MDMX in human cancers. Graphical representation of the expression levels of MDM2 (upper panel) and MDMX (lower panel) in human cancers obtained from studies collected in cBioPortal For Cancer Genomics (www.cbioportal.org). The picture shows RNA values of patients expressing the wild-type or mutated genes. TCGA The Cancer Genome Atlas Network

Fig. 2

Schematic representation of the autoregulatory loop between P53, MDM2, and MDMX and pharmacological inhibitors. The picture shows the main molecular links between P53, MDM2, and MDMX together with the MDM2 and MDMX inhibitors under clinical evaluation and the key compounds used in clinical studies for combination therapy