1531P - Nuclear factor-kappa b as a molecular target in malignant pleural mesothelioma

Date 30 September 2012
Event ESMO Congress 2012
Session Poster presentation II
Topics Mesothelioma
Translational Research
Presenter Kathy Gately
Authors K.A. Gately1, E. Jennions2, P. Godwin3, M. Barr4, S. Heavey5, K. Umezawa6, J. Edwards7, S.G. Gray4, K.J. O'Byrne8
  • 1Clinical Medicine, St James's Hospital, 8 - Dublin/IE
  • 2Oncology, University of Leicester, Leicester/UK
  • 3Clinical Medicine, Trinity College Dublin, Dublin/IE
  • 4Clinical Medicine, Trinity College Dublin, D8 - Dublin/IE
  • 5Trinity College Dublin, 8 - Dublin/IE
  • 6Oncology, Keio University, Yokohama/JP
  • 7Department Of Cardiothoracic Surgery, Sheffield Thoracic Institute, Sheffield/UK
  • 8Hope Directorate, St James's Hospital, Dublin/IE

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer associated with exposure to asbestos. Currently rates of MPM are rising and estimates indicate that the incidence of MPM will peak within the next 10-15 years for the western world. Untreated, MPM has a median survival time of 6 months, and most patients die within 24 months of diagnosis. Nuclear Factor kappa B (NFkB) is a pro-inflammatory transcription factor often described as the master regulator of pro-inflammatory responses within the cellular setting. We and others have shown that NF?B is linked to cisplatin resistance (abstract 2307). Several lines of evidence also link NFkB to the pathogenesis of MPM.

Using IHC we examined the expression of NFkB in a cohort of MPM patients (n = 200) and correlated expression with various clinicopathological variables. Cytoplasmic or membranous immunostaining was seen in the majority of tumour samples (96.5%), but nuclear localisation of NFkB was seen in only 11% cases. There was no significant correlation between the level of expression of NFkB and standard clinicopathological prognostic factors. Kaplan-Meier Survival analysis showed that nuclear NFkB expression correlated with reduced survival with (p = 0.05). NFkB was expressed in all MPM cell lines tested to a varying extent (n = 20), with no associations to histology. Although small-molecule inhibitors of NFkB have been proposed as single-agent therapies for cancers with aberrant NFkB activity, most classic NFkB inhibitors are poorly selective and result in off-target effects. Dehydroxymethyl-epoxyquinomicin (DHMEQ) is a novel NFkB inhibitor of low molecular weight designed from the structure of the antibiotic epoxyquinomicin C. When bound DHMEQ irreversibly inhibits NFkB and prevents its translocation to the nucleus. A series of MPM cell lines including a panel of isogenic parent/cisplatin resistant cell lines were treated with various concentrations of DHMEQ. The effects of DHMEQ on cellular viability were examined using various methodologies (including multi-parametric High Content Screening) and the results will be presented at the meeting.

Disclosure

All authors have declared no conflicts of interest.