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L. Quinn
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P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.08-013 - Long Non-Coding RNAs Associated with Lysine Demethylases Are Overexpressed and Epigenetically Regulated in Malignant Pleural Mesothelioma (ID 1757)
09:30 - 09:30 | Author(s): L. Quinn
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is an aggressive rare cancer affecting the pleura and is predominatly associated with prior exposure to asbestos. Treatment options are limited, and most patients die within 24 months of diagnosis. The current standard of care for MPM patients is a combination of cisplatin and pemetrexed (or alternatively cisplatin and raltitrexed), yet most patients die within 24 months of diagnosis. Lysine Demethylases (KDMs) containing a JmjC domain regulate gene expression by “erasing or removing” methylation on histones in chromatin. Members of this family are frequently found to have aberrant expression in cancer and currently are actively pursued as candidate pharmaceutical therapeutic targets. We have shown that various members of the JmjC family of KDMs have significantly altered expression in MPM. Long non-coding RNAs (lncRNAs) belong to a group of RNAs that are usually more than 200 nucleotides long and play important roles in different regulatory processes, including regulation of gene expression. Several lncRNAs have also been shown to play a role as oncogenic molecules in different cancer cells (one example being HOTAIR). Altered expression of lncRNAS therefore make them candidate biomarkers with diagnostic and therapeutic potential in cancer. Several such lncRNAs have now been shown to locate to the same chromosomal region as various KDMs. These are KDM4A/KDM4A-AS1, KDM5B/KDM5B-AS1 (also known as PCAT6), KDM5C/ AY927613.1 and JARID2/JARID2-AS1. We therefore examined the expression of these lncRNAs in MPM.
Methods:
A panel of MPM cell lines were screened for expression of KDM4A-AS1, KDM5B-AS1, AY927613.1 and JARID2-AS1 by RT-PCR. lncRNA transcript levels were subsequently examined by RT-PCR in a cohort of snap-frozen patient samples isolated at surgery comprising benign, epithelial, biphasic, and sarcomatoid histologies. The effects of KDM and HDAC inhibitors on their expression was also examined.
Results:
The expression of the various lncRNAs was detectable across our panel of cell lines. In primary tumours the expression of these lncRNAs 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.
Conclusion:
The expression of these lncRNAs are significantly altered in MPM. We have cloned KDM4A-AS1 and PCAT6 into overexpression constructs and future studies will assess the effects of these lncRNAs overexpression on mesothelioma proliferation, cellular health and gene expression to determine their potential role in mesothelioma.
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P2.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 225)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.08-006 - The JmjC Family of Lysine Demethylases Are Overexpressed and Potential Therapeutic Targets in Malignant Pleural Mesothelioma (ID 1753)
09:30 - 09:30 | Author(s): L. Quinn
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is an aggressive rare cancer affecting the pleura and is predominatly associated with prior exposure to asbestos. Treatment options are limited, and most patients die within 24 months of diagnosis. The current standard of care for MPM patients is a combination of cisplatin and pemetrexed (or alternatively cisplatin and raltitrexed), yet most patients die within 24 months of diagnosis. There is therefore an urgent unmet need to identify new therapeutic options for the treatment of MPM. Asbestos fibres contain of transition metals and their ability to both adsorb and accumulate these metals was one of the first mechanisms suggested for explaining the toxic and particularly carcinogenic effects of asbestos. One of the transition metals in asbestos fibres is iron, and therefore asbestos fibres 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 by “erasing or removing” methylation on histones in chromatin. Members of this family are frequently found to have aberrant expression in cancer and currently are actively pursued as candidate pharmaceutical therapeutic targets. Given that asbestos increases iron levels, this may result in aberrant KDM activity, and these KDMs could therefore be novel candidate targets in mesothelioma. We therefore examined the expression of several JmjC containing KDMs in MPM and assessed their potential for therapeutic intervention in mesothelioma using existing small molecule inhibitors.
Methods:
A panel of MPM cell lines were screened for expression of KDM4A-D, KDM5A/B and KDM6A/B by RT-PCR. mRNA levels were subsequently examined by RT-PCR in a cohort of snap-frozen patient samples isolated at surgery comprising benign, epithelial, biphasic, and sarcomatoid histologies. IHC was performed for KDM4A 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.
Results:
The expression of the various KDMs was detectable across our panel of cell lines. In primary tumours the expression of these KDMs 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 KDMs are significantly altered in MPM. Small molecule inhibitors directed against these KDMs 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.
