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The “Guardian Of The Genome” p53 In Pancreatic Cancer

Curator: David Orchard-Webb, PhD

 

A recent next generation sequencing (NGS) study of PDAC samples found that the “guardian of the genome” p53 (TP53) had a total mutation rate of 50% (the literature suggests up to 75%) [1]. TP53 deletions occurred in 6% of samples. Missense mutation of p53 (44% of samples) can convert it from a tumour suppressor to a neo-oncogene. This curation collates recent articles of note with reference to p53 including function, drug development, and prognostics in pancreatic ductal adenocarcinoma (PDAC).

 

Vaccines

 

Katchman, Benjamin A., Rodrigo Barderas, Rizwan Alam, Diego Chowell, Matthew S. Field, Laura J. Esserman, Garrick Wallstrom, et al. ‘Proteomic Mapping of p53 Immunogenicity in Pancreatic, Ovarian, and Breast Cancers’. Proteomics. Clinical Applications, 28 April 2016. doi:10.1002/prca.201500096.

 

Terashima, Takeshi, Eishiro Mizukoshi, Kuniaki Arai, Tatsuya Yamashita, Mariko Yoshida, Hajime Ota, Ichiro Onishi, et al. ‘P53, hTERT, WT-1, and VEGFR2 Are the Most Suitable Targets for Cancer Vaccine Therapy in HLA-A24 Positive Pancreatic Adenocarcinoma’. Cancer Immunology, Immunotherapy: CII 63, no. 5 (May 2014): 479–89. doi:10.1007/s00262-014-1529-8.

 

Drug targeting p53

 

Xu, Jing, Amit Singh, and Mansoor M. Amiji. ‘Redox-Responsive Targeted Gelatin Nanoparticles for Delivery of Combination Wt-p53 Expressing Plasmid DNA and Gemcitabine in the Treatment of Pancreatic Cancer’. BMC Cancer 14, no. 1 (2014): 75. http://www.biomedcentral.com/1471-2407/14/75/.

 

Camp, E R, C Wang, E C Little, P M Watson, K F Pirollo, A Rait, D J Cole, E H Chang, and D K Watson. ‘Transferrin Receptor Targeting Nanomedicine Delivering Wild-Type p53 Gene Sensitizes Pancreatic Cancer to Gemcitabine Therapy’. Cancer Gene Therapy 20, no. 4 (April 2013): 222–28. doi:10.1038/cgt.2013.9.

 

Izetti, Patricia, Agnes Hautefeuille, Ana Lucia Abujamra, Caroline Brunetto de Farias, Juliana Giacomazzi, Bárbara Alemar, Guido Lenz, et al. ‘PRIMA-1, a Mutant p53 Reactivator, Induces Apoptosis and Enhances Chemotherapeutic Cytotoxicity in Pancreatic Cancer Cell Lines’. Investigational New Drugs 32, no. 5 (October 2014): 783–94. doi:10.1007/s10637-014-0090-9.

 

Takei, Y., S. Okamoto, K. Kawamura, Y. Jiang, T. Morinaga, M. Shingyoji, I. Sekine, et al. ‘Expression of p53 Synergistically Augments Caspases-Mediated Apoptosis Induced by Replication-Competent Adenoviruses in Pancreatic Carcinoma Cells’. Cancer Gene Therapy 22, no. 9 (September 2015): 445–53. doi:10.1038/cgt.2015.33.

 

Li, Jinluan, Jianji Pan, Xianggao Zhu, Ying Su, Lingling Bao, Sufang Qiu, Changyan Zou, Yong Cai, Junxin Wu, and Ivan WK Tham. ‘Recombinant Adenovirus-p53 (Gendicine) Sensitizes a Pancreatic Carcinoma Cell Line to Radiation’. Chinese Journal of Cancer Research 25, no. 6 (2013): 715. http://www.cjcrcn.org/article/html_3076.html.

 

Hastie, Eric, Marcela Cataldi, Nury Steuerwald, and Valery Z. Grdzelishvili. ‘An Unexpected Inhibition of Antiviral Signaling by Virus-Encoded Tumor Suppressor p53 in Pancreatic Cancer Cells’. Virology 483 (September 2015): 126–40. doi:10.1016/j.virol.2015.04.017.

 

The Impact of p53 Status on Therapy

 

Kurahara, Hiroshi, Kosei Maemura, Yuko Mataki, Masahiko Sakoda, Hiroyuki Shinchi, and Shoji Natsugoe. ‘Impact of p53 and PDGFR-β Expression on Metastasis and Prognosis of Patients with Pancreatic Cancer’. World Journal of Surgery, 3 March 2016. doi:10.1007/s00268-016-3477-2.

 

Xiang, Jin-Feng, Wen-Quan Wang, Liang Liu, Hua-Xiang Xu, Chun-Tao Wu, Jing-Xuan Yang, Zi-Hao Qi, et al. ‘Mutant p53 Determines Pancreatic Cancer Poor Prognosis to Pancreatectomy through Upregulation of Cavin-1 in Patients with Preoperative Serum CA19-9 ≥ 1,000 U/mL’. Scientific Reports 6 (12 January 2016): 19222. doi:10.1038/srep19222.

 

Rajeshkumar, N. V., Prasanta Dutta, Shinichi Yabuuchi, Roeland F. de Wilde, Gary V. Martinez, Anne Le, Jurre J. Kamphorst, et al. ‘Therapeutic Targeting of the Warburg Effect in Pancreatic Cancer Relies on an Absence of p53 Function’. Cancer Research 75, no. 16 (15 August 2015): 3355–64. doi:10.1158/0008-5472.CAN-15-0108.

 

Fiorini, Claudia, Marco Cordani, Chiara Padroni, Giovanni Blandino, Silvia Di Agostino, and Massimo Donadelli. ‘Mutant p53 Stimulates Chemoresistance of Pancreatic Adenocarcinoma Cells to Gemcitabine’. Biochimica et Biophysica Acta (BBA) – Molecular Cell Research 1853, no. 1 (January 2015): 89–100. doi:10.1016/j.bbamcr.2014.10.003.

 

TP53 Function in Pancreatic Cancer

 

Bailey, J M, A M Hendley, K J Lafaro, M A Pruski, N C Jones, J Alsina, M Younes, et al. ‘p53 Mutations Cooperate with Oncogenic Kras to Promote Adenocarcinoma from Pancreatic Ductal Cells’. Oncogene, 23 November 2015. doi:10.1038/onc.2015.441.

 

Sheng, Weiwei, Ming Dong, Jianping Zhou, Xin Li, Qingfeng Liu, Qi Dong, and Feng Li. ‘Cooperation among Numb, MDM2 and p53 in the Development and Progression of Pancreatic Cancer’. Cell and Tissue Research 354, no. 2 (November 2013): 521–32. doi:10.1007/s00441-013-1679-6.

 

Weissmueller, Susann, Eusebio Manchado, Michael Saborowski, John P. Morris, Elvin Wagenblast, Carrie A. Davis, Sung-Hwan Moon, et al. ‘Mutant p53 Drives Pancreatic Cancer Metastasis through Cell-Autonomous PDGF Receptor β Signaling’. Cell 157, no. 2 (April 2014): 382–94. doi:10.1016/j.cell.2014.01.066.

 

Morton, J. P., P. Timpson, S. A. Karim, R. A. Ridgway, D. Athineos, B. Doyle, N. B. Jamieson, et al. ‘Mutant p53 Drives Metastasis and Overcomes Growth Arrest/senescence in Pancreatic Cancer’. Proceedings of the National Academy of Sciences 107, no. 1 (5 January 2010): 246–51. doi:10.1073/pnas.0908428107.

 

Hamilton, Garth, Aswin G. Abraham, Jennifer Morton, Oliver Sampson, Dafni E. Pefani, Svetlana Khoronenkova, Anna Grawenda, et al. ‘AKT Regulates NPM Dependent ARF Localization and p53mut Stability in Tumors’. Oncotarget 5, no. 15 (2014): 6142–6167. http://eprints.gla.ac.uk/102649.

 

Sadagopan, S, M V Veettil, S Chakraborty, N Sharma-Walia, N Paudel, V Bottero, and B Chandran. ‘Angiogenin Functionally Interacts with p53 and Regulates p53-Mediated Apoptosis and Cell Survival’. Oncogene 31, no. 46 (15 November 2012): 4835–47. doi:10.1038/onc.2011.648.

 

TP53 and Epithelial Mesenchymal Transition (EMT)

 

Wörmann, Sonja M., Liang Song, Jiaoyu Ai, Kalliope N. Diakopoulos, Kivanc Görgülü, Dietrich Ruess, Andrew Campbell, et al. ‘Loss of P53 Function Activates JAK2-STAT3 Signaling to Promote Pancreatic Tumor Growth, Stroma Modification, and Gemcitabine Resistance in Mice and Is Associated With Patient Survival’. Gastroenterology, 18 March 2016. doi:10.1053/j.gastro.2016.03.010.

 

Lee, Sun-Hye, Su-Jin Lee, Yeon Sang Jung, Yongbin Xu, Ho Sung Kang, Nam-Chul Ha, and Bum-Joon Park. ‘Blocking of p53-Snail Binding, Promoted by Oncogenic K-Ras, Recovers p53 Expression and Function’. Neoplasia 11, no. 1 (January 2009): 22–IN6. doi:10.1593/neo.81006.

 

Pancreatic Cancer Risk Factor

 

Sonoyama, Takayuki. ‘TP53 Codon 72 Polymorphism Is Associated with Pancreatic Cancer Risk in Males, Smokers and Drinkers’. Molecular Medicine Reports, 8 March 2011. doi:10.3892/mmr.2011.449.

 

3D PDAC in vitro Culture Models

 

Huang, Ling, Audrey Holtzinger, Ishaan Jagan, Michael BeGora, Ines Lohse, Nicholas Ngai, Cristina Nostro, et al. ‘Ductal Pancreatic Cancer Modeling and Drug Screening Using Human Pluripotent Stem Cell– and Patient-Derived Tumor Organoids’. Nature Medicine 21, no. 11 (26 October 2015): 1364–71. doi:10.1038/nm.3973.

 

REFERENCES

 

1. Witkiewicz, Agnieszka K., Elizabeth A. McMillan, Uthra Balaji, GuemHee Baek, Wan-Chi Lin, John Mansour, Mehri Mollaee, et al. ‘Whole-Exome Sequencing of Pancreatic Cancer Defines Genetic Diversity and Therapeutic Targets’. Nature Communications 6 (9 April 2015): 6744. doi:10.1038/ncomms7744.

 

Other Related Articles Published In This Open Access Online Journal Include The Following:

 

https://pharmaceuticalintelligence.com/2015/12/27/p53-tumor-drug-resistance-mechanism-target/