Abstract 522: Cooperative effect of the TLR3-agonist Poly(A:U) combined to a Smac-mimetic against malignant nasopharyngeal carcinomas cells
Authors: Benjamin Verillaud, Michel Wassef, Marie-Paule Sablin, Pierre Busson
Journal: Cancer Research (2012)

Abstract Nasopharyngeal carcinomas (NPC) are malignant epithelial tumors of the nasopharyngeal cavity. They are consistently associated with the Epstein-Barr virus (EBV). Though NPCs are on average more radiosensitive and chemosensitive than other tumors of the upper aero-digestive tract, many therapeutic challenges remain. In this context the development of therapeutic approaches taking better account of biological characteristics of NPC and well defined biological targets remains a priority. We have previously reported a cooperative effect of the TLR3-agonist poly(I:C) combined to a Smac-mimetic against NPC cells. (Friboulet et al., Neoplasia 2008, 10: 1183-1194 and BMC cancer 2010, 10: 327). However Poly(I:C) is a ligand not only for the TLR3 but also other receptors of double-stranded RNAs, like RIG1 and PKR. In contrast Poly(A:U) is much more specific for TLR3. In addition, Poly(A:U) has less secondary effects in patients and has already been successfully used in a phase III clinical trial against breast cancer (Salaun et al., Cancer Res. 201, 71: 1607-14). Therefore one aim of this study was to explore the therapeutic potential of the treatment of NPC cells by Poly(A:U) combined to an inhibitor of IAPs (“inhibitor of apoptosis proteins”). Another aim was to assess the expression of TLR3 by NPC cells, an aspect of their phenotype which - to our knowledge - has never been previously described. The expression of TLR3 was assessed in a series of EBV-positive NPC tumor lines (C666-1, C15, C17, C18) and a series of NPC clinical specimens by Western blot and immunohistochemistry, respectively. In vitro TLR3 was consistently detected in malignant NPC cells at a high level by comparison with non-NPC control lines. In all NPC biopsies, TLR3 expression was detected in a substantial fraction of malignant NPC cells. The effects of poly(A:U) as single agents were tested on the EBV-positive NPC cells lines C666-1 without significant effects on cell growth and cell survival at least at concentrations compatible with clinical use. In contrast, growth inhibition and apoptosis induction were obtained by combination of Poly(A:U) with RMT 5265, an IAP inhibitor based on Smac-mimicry which targets c-IAP1, c-IAP2 and XIAP. It is noteworthy that these effects were obtained using concentrations of Poly(A:U) of 1 μg/ml or less and concentrations of the IAP inhibitor (RMT 5265) of 100 nM or less. These data confirm that TLR3 expression is a factor of vulnerability for NPC cells as it is the case for other head and neck carcinomas (Rydberg et al., Immunology 2009, 128: e601–e611; Umemura et al., Cancer Res. Online 2011). Until now, Smac mimetics and Poly(A:U) have been the subject of separate therapeutic trials. In light of our observations, combined use of both types of compounds should be considered for treatment of EBV-associated nasopharyngeal carcinomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 522. doi:1538-7445.AM2012-522