MDM2-p53 Interaction in Paediatric Solid Tumours: Preclinical Rationale, Biomarkers and Resistance

Abstract

p53 is one of the main regulators of apoptosis, senescence, cell cycle arrest and DNA repair. The expression, function and stabilization of p53 are governed by a complex network of regulators including p14(ARF) and MDM2. MDM2 is the main negative regulator of p53 activity and stability. Unlike tumours in adults, which tend to overcome p53 regulation by p53 mutations, the paediatric tumours neuroblastoma and sarcoma frequently retain wild type p53. Nevertheless, in childhood cancer the p53 pathway is commonly impaired due to upstream MDM2-p14(ARF)-p53 network aberrations. In contrast, aberrations of the p53 downstream pathway are very rare. In cancer cells with intact p53 downstream function MDM2 inhibition, and subsequent rapid increases in nuclear p53 levels, potently "re-activate" dormant apoptotic pathways and rapidly induce apoptotic cell death. As a result MDM2-p53 interaction inhibitors, including cis-imidazolines analogs (Nutlins), are potentially very effective agents in neuroblastoma and sarcomas. Predictive biomarkers are important as a lack of p53 mutations appears to reliably predict response to these inhibitors. Tumours should be screened for p53 mutations in children considered for MDM2-p53 interaction inhibitors. In addition, it is essential that other predictive biomarkers are investigated. The serum concentration of macrophage inhibitory cytokine- 1 (MIC-1) may be a good pharmacodynamic biomarker based on recent findings. In conclusion, targeting the interaction between p53 and its main negative regulator MDM2 represents a major new therapeutic approach in poor prognosis paediatric malignancies without p53 mutations.

Mdm2 and p53 Expression in Radiation-Induced Sarcomas of the Head and Neck: Comparison with <i>De Novo</i> Sarcomas

“…The Mdm2-p53 interaction in sarcomas has recently received attention on account of a new therapeutic approach targeting this interaction[10,11,16]. MDM2 amplification/overexpression is characteristic of well-differentiated/dedifferentiated liposarcomas (DDLS), but is also identified in a small percentage of other sarcomas[17,18].…”

“…RMSs are aggressive pediatric tumors, and there have been recent preclinical trials of Mdm2 inhibitors in RMS[10,11]. Radiation-induced RMS has rarely been described, mostly among Chinese patients treated for nasopharyngeal cancer[8,9,19,20].…”

“…The poor prognosis and therapeutic difficulties of RISs have been described by many researchers[5-9]. Recently, Mdm2 inhibitors have emerged as novel therapeutic agents for some sarcomas[10,11]. Immunohistochemical examinations of Mdm2 expression in RIS have not been published to date.…”

Role of wild-type p53-induced phosphatase 1 in cancer

“…Overexpression of Wip1 in neuroblastoma may repress p53 function by two signaling pathways, one is the Wip1-p53 pathway, and the other is the Wip1-Mdm2-p53 pathway (35), resulting in tumorigenesis. In addition, a previous report demonstrated that Wip1 was significantly overexpressed in 56% of cancer tissues, and promoted tumor progression to a higher stage, poor prognosis and chemotherapy resistance (Table I) (32).…”

Polymeric Nanoparticles to Combat Squamous Cell Carcinomas in Patients with Dystrophic Epidermolysis Bullosa

“…A recent patent utilizing certain small molecule compounds prevents p53 downregulation by inhibiting its interaction with the MDM2 protein [29]. MDM2 is a known suppressor of p53, and by selectively inhibiting its ability to function, the patent aims to restore normal p53 function [30]. …”