Pre-activation of the p53 pathway through Nutlin-3a sensitises sarcomas to drozitumab therapy.

Abstract	The present study evaluated the efficacy of drozitumab, a human monoclonal agonistic antibody directed against death receptor 5 (DR5), as a new therapeutic avenue for the targeted treatment of bone and soft-tissue sarcomas. The antitumour activity of drozitumab as a monotherapy or in combination with Nutlin-3a was evaluated in a panel of sarcoma cell lines in vitro and human sarcoma patient samples ex vivo. Knockdown experiments were used to investigate the central role of p53 as a regulator of drozitumab cytotoxicity. Pre-activation of the p53 pathway through Nutlin-3a upregulated DR5, subsequently sensitising sarcoma cell lines and human sarcoma specimens to the pro-apoptotic effects of drozitumab. Silencing of p53 strongly decreased DR5 mRNA expression resulting in abrogation of drozitumab-induced apoptosis. Our study provides the first pre-clinical evaluation of combination therapy using p53-activating agents with drozitumab to further sensitise sarcomas to the cytotoxic effects of DR5 antibody therapy.
Authors	Kathleen I Pishas, Susan J Neuhaus, Mark T Clayer, Alaknanda Adwal, Michael P Brown, Andreas Evdokiou, David F Callen, Paul M Neilsen
Journal	Oncology reports (Oncol Rep) Vol. 30 Issue 1 Pg. 471-7 (Jul 2013) ISSN: 1791-2431 [Electronic] Greece
PMID	23670273 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antibodies, Monoclonal Antibodies, Monoclonal, Humanized Imidazoles Piperazines RNA, Messenger RNA, Small Interfering Receptors, TNF-Related Apoptosis-Inducing Ligand TP53 protein, human Tumor Suppressor Protein p53 nutlin 3 drozitumab
Topics	Antibodies, Monoclonal (pharmacology) Antibodies, Monoclonal, Humanized Apoptosis (drug effects) Cell Line, Tumor Humans Imidazoles (metabolism) Piperazines (metabolism) RNA Interference RNA, Messenger (biosynthesis) RNA, Small Interfering Receptors, TNF-Related Apoptosis-Inducing Ligand (genetics, immunology, metabolism) Sarcoma (drug therapy, metabolism) Tumor Suppressor Protein p53 (genetics, metabolism)

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