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MDM2-p53 interaction in paediatric solid tumours: preclinical rationale, biomarkers and resistance

(2014) CURRENT DRUG TARGETS. 15(1). p.114-123
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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 p14ARF 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-p14ARF-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.
Keywords
MDM2, Nutlins, paediatric cancer, novel agents, p53, sarcomas, neuroblastoma, retinoblastoma, WILD-TYPE P53, DIRECT TRANSCRIPTIONAL TARGET, DNA-DAMAGE RESPONSE, ANTAGONIST NUTLIN-3, INTERGROUP RHABDOMYOSARCOMA, NEUROBLASTOMA-CELLS, CANCER-CELLS, P53/MDM2/P14(ARF) PATHWAY, SENSITIZES NEUROBLASTOMA, MYCN AMPLIFICATION

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Citation

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Chicago
Barone, Giuseppe, Deborah A Tweddle, Jason M Shohet, Louis Chesler, Lucas Moreno, Andrew DJ Pearson, and Tom Van Maerken. 2014. “MDM2-p53 Interaction in Paediatric Solid Tumours: Preclinical Rationale, Biomarkers and Resistance.” Current Drug Targets 15 (1): 114–123.
APA
Barone, Giuseppe, Tweddle, D. A., Shohet, J. M., Chesler, L., Moreno, L., Pearson, A. D., & Van Maerken, T. (2014). MDM2-p53 interaction in paediatric solid tumours: preclinical rationale, biomarkers and resistance. CURRENT DRUG TARGETS, 15(1), 114–123.
Vancouver
1.
Barone G, Tweddle DA, Shohet JM, Chesler L, Moreno L, Pearson AD, et al. MDM2-p53 interaction in paediatric solid tumours: preclinical rationale, biomarkers and resistance. CURRENT DRUG TARGETS. 2014;15(1):114–23.
MLA
Barone, Giuseppe, Deborah A Tweddle, Jason M Shohet, et al. “MDM2-p53 Interaction in Paediatric Solid Tumours: Preclinical Rationale, Biomarkers and Resistance.” CURRENT DRUG TARGETS 15.1 (2014): 114–123. Print.
@article{4228972,
  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 p14ARF 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-p14ARF-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 {\textacutedbl}re-activate{\textacutedbl} 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.},
  author       = {Barone, Giuseppe and Tweddle, Deborah A and Shohet, Jason M and Chesler, Louis and Moreno, Lucas and Pearson, Andrew DJ and Van Maerken, Tom},
  issn         = {1389-4501},
  journal      = {CURRENT DRUG TARGETS},
  keyword      = {MDM2,Nutlins,paediatric cancer,novel agents,p53,sarcomas,neuroblastoma,retinoblastoma,WILD-TYPE P53,DIRECT TRANSCRIPTIONAL TARGET,DNA-DAMAGE RESPONSE,ANTAGONIST NUTLIN-3,INTERGROUP RHABDOMYOSARCOMA,NEUROBLASTOMA-CELLS,CANCER-CELLS,P53/MDM2/P14(ARF) PATHWAY,SENSITIZES NEUROBLASTOMA,MYCN AMPLIFICATION},
  language     = {eng},
  number       = {1},
  pages        = {114--123},
  title        = {MDM2-p53 interaction in paediatric solid tumours: preclinical rationale, biomarkers and resistance},
  url          = {http://dx.doi.org/10.2174/13894501113149990194},
  volume       = {15},
  year         = {2014},
}

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