Author of

• 20158

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  P1.09 - Mesothelioma (ID 695)

  • Event: WCLC 2017
  • Type: Poster Session with Presenters Present
  • Track: Mesothelioma
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)

  • 22728

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    P1.09-006 - JMJ and BRD Domain Family Members in Malignant Pleural Mesothelioma: Potential Therapeutic Targets or Not? (ID 9919)

    09:30 - 09:30  |  Author(s): G. Roche
    • Abstract

    Background:
    Malignant pleural mesothelioma (MPM) is an aggressive rare cancer affecting the pleura and is predominantly associated with prior exposure to asbestos. Treatment options are limited, and most patients die within 24 months of diagnosis. There is an urgent unmet need to identify new therapeutic options for the treatment of MPM. Asbestos fibres contain transition metals such as iron, and may cause an alteration of iron homeostasis in the tissue. In addition, asbestos fibres have also been shown to have high affinity for histones, and therefore may result in high accumulation of iron around chromatin. Lysine Demethylases (KDMs) containing a JmjC domain require both Fe2+ and 2-oxoglutarate as co-factors to regulate gene expression. Bromodomain containing proteins a family of chromatin reader proteins, have potential therapeutic efficacy against various malignancies. Long non-coding RNAs (lncRNAs) have also been shown to play a role as oncogenic molecules in different cancers. Several such lncRNAs have now been shown to locate to the same chromosomal region as various KDMs. We therefore examined the expression of various JmjC and Brd members (along with any associated lncRNAs) in MPM and assessed some for their clinical potential using existing small molecule inhibitors.
    
    Method:
    A panel of MPM cell lines and a cohort of snap-frozen patient samples isolated at surgery comprising benign, epithelial, biphasic, and sarcomatoid histologies were screened for expression of various BRD and JmjC members and associated lncRNAs by RT-PCR. IHC for KDM4A was performed on a cohort of FFPE specimens. The effects of treatments with small molecule inhibitors targeting these proteins on both cellular health and gene expression were assessed.
    
    Result:
    The expression of the various KDMs was detectable across our panel of cell lines. In primary tumours the expression of many of these genes were significantly elevated in malignant MPM compared to benign pleura (p<0.05), and significant differences were also observed when samples were analysed across different histological subtypes. Treatment of mesothelioma cell lines with various small molecule inhibitors caused significant effects on cellular health and on the expression of a panel of genes.
    
    Conclusion:
    The expression of various KDMs, BRD genes and associated lncRNAs are significantly altered in MPM. Small molecule inhibitors directed against these show potential therapeutic efficacy with significant anti-proliferative effects. We continue to assess the effects of these compounds on gene expression and cellular health to confirm their potential utility as novel therapies for the treatment of MPM.