Critical review about MDM2 in cancer: Possible role in malignant mesothelioma and implications for treatment

Our plain-English summary of Critical review about MDM2 in cancer: Possible role in malignant mesothelioma and implications for treatment, by L. Urso, F. Calabrese, A. Favaretto, et al (Critical Reviews in Oncology/hematology, 2016).

The study

• Authors: L. Urso, F. Calabrese, A. Favaretto, P. Conte, G. Pasello
• Journal: Critical Reviews in Oncology/hematology
• Published: 2016;97:220-30
• Type of article: Review
• Cited by: 43 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The tumor suppressor p53 regulates genes involved in DNA repair, metabolism, cell cycle arrest, apoptosis and senescence. p53 is mutated in about 50% of the human cancers, while in tumors with wild-type p53 gene, the protein function may be lost because of overexpression of Murine Double Minute 2 (MDM2). MDM2 targets p53 for ubiquitylation and proteasomal degradation. p53 reactivation through MDM2 inhibitors seems to be a promising strategy to sensitize p53 wild-type cancer cells to apoptosis. Moreover, additional p53-independent molecular functions of MDM2, such as neoangiogenesis promotion, have been suggested. Thus, MDM2 might be a target for anticancer treatment because of its antiapoptotic and proangiogenetic role. Malignant pleural mesothelioma (MPM) is an aggressive asbestos-related tumor where wild-type p53 might be present. The present review gives a complete landscape about the role of MDM2 in cancer pathogenesis, prognosis and treatment, with particular focus on Malignant Pleural Mesothelioma.

Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

In plain English

This was a narrative review of published research on MDM2, a protein that tags the tumor-suppressor protein p53 for breakdown. It covered MDM2 across many cancers, with particular focus on malignant pleural mesothelioma, which the authors described as an asbestos-related tumor. The authors noted that only a few studies had examined MDM2 in mesothelioma. In one study they reviewed, MDM2 overexpression was found in 50.8% of 55 mesothelioma samples and was linked with asbestos exposure, but not with survival. In another study, of 61 patients, no MDM2-positive patients were alive at three years, against 32% three-year survival for MDM2-negative patients. The authors' own earlier laboratory work found a stronger combined anticancer effect of an MDM2 inhibitor plus a TRAIL agonist in sarcomatoid mesothelioma cells. Drugs blocking the MDM2-p53 link had been tested only in phase I trials. The authors said the existing data did not allow any conclusion on MDM2's role in mesothelioma. Even so, they concluded that the evidence would suggest MDM2 as a promising therapeutic target in mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: narrative review of published laboratory and clinical studies
• Who was studied: Published studies on MDM2 in various cancers, focusing on the few studies of MDM2 in malignant pleural mesothelioma (MPM); written by authors in Padova, Italy
• Exposure: No exposure was studied. The review concerned the MDM2 protein and drugs that block it. Asbestos was mentioned only as the cause of MPM, and no fiber types were named.
• Main results:
  • In a reviewed study (Bahnassy et al., 2012) of 55 MPM samples, MDM2 overexpression was seen in 50.8% of tumor samples. It correlated with asbestos exposure but had no prognostic significance.
  • In a reviewed study (Mairinger et al., 2014) of 61 MPM patients, MDM2-negative MPM had 3-year survival of 32%, while no patients with MDM2-positive MPM were alive after three years.
  • The authors' own earlier preclinical work showed a higher combined (synergistic) anticancer effect of an MDM2 inhibitor plus a TRAIL agonist in sarcomatoid MPM cells. In their tumor samples they observed only a trend towards a negative prognostic role of MDM2.
  • MDM2-p53 inhibitor drugs had been investigated only in phase I clinical trials.
• The authors' conclusion: The authors concluded that the reported evidence would suggest MDM2 as a promising therapeutic target in mesothelioma, because of its antiapoptotic and pro-mitogenic function and its connection with new blood vessel formation.
• Limitations the authors state:
  • The available MPM data do not allow any conclusion on MDM2's role, because the populations were heterogeneous, few patients had sarcomatoid MPM, and treatments (especially surgery) differed.
  • No evidence of MDM2 involvement in new blood vessel formation had yet been described in MPM.
  • There is no shared detection method or scoring for MDM2 overexpression in tumor samples.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Apoptosis, Pleural Mesothelioma, Prognosis.

Related studies

• Mdm2 protein expression is strongly associated with survival in malignant pleural mesothelioma — F.D. Mairinger, R.F. Walter, et al. (2014)
• The p53/mouse double minute 2 homolog complex deregulation in merlin-deficient tumours — S. Ammoun, M.C. Schmid, et al. (2015)
• Combination of a p53-activating CP-31398 and an MDM2 or a FAK inhibitor produces growth suppressive effects in mesothelioma with wild-type p53 genotype — B. Zhong, M. Shingyoji, et al. (2020)
• Imaging of malignant pleural mesothelioma: it is possible a screening or early diagnosis program?-a systematic review about the use of screening programs in a population of asbestos exposed workers — F. Falaschi, C. Romei, et al. (2018)
• Effect of mineral particles containing iron on primary cultures of rabbit tracheal epithelial cells: possible implication of oxidative stress — C. Guilianelli, A. Baeza-Squiban, et al. (1993)
• Ascorbic acid modifies the surface of asbestos: possible implications in the molecular mechanisms of toxicity — G. Martra, M. Tomatis, et al. (2003)

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