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S. Cregan
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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): S. Cregan
- 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.
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P3.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 226)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.08-008 - Tip60 (KAT5) May Be a Candidate for Therapeutic Targeting in Malignant Pleural Mesothelioma (ID 1760)
09:30 - 09:30 | Author(s): S. Cregan
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is a rare aggressive cancer of the pleura. The most well established risk factor for this disease is exposure to asbestos. The current standard of care for patients suffering from MPM is a combination of cisplatin and pemetrexed (or alternatively cisplatin and raltitrexed). Most patients however, die within 24 months of diagnosis. New therapies are therefore urgently required for this disease. KAT5 (also known as Tip60) is the catalytic subunit of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of select genes. This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair. KAT5 has also been linked with the development of cisplatin resistance. KAT5 may therefore be a significant element in MPM with respect to responses to cisplatin based therapy and could represent a novel candidate target for intervention.
Methods:
KAT5 has 4 variant mRNAs. Primers were designed to distinguish between all variants, and a panel of MPM cell lines was screened for KAT5 expression by RT-PCR. Levels of KAT5 were subsequently examined in a cohort of snap-frozen patient samples isolated at surgery comprising benign, epithelial, biphasic, and sarcomatoid histologies by RT-PCR. The effects of a small molecule inhibitor of KAT5 (MG-149) on cellular proliferation were examined.
Results:
Semi-quantitative densitometric analysis showed that the expression of KAT5 is dramatically increased in MPM for all mRNA variants. When separated according to histological subtype, significant differences were also observed between the various histologies. A small molecule inhibitor of KAT5 exists and treatment of cells with this small molecule inhibitor (MG-149) resulted in a significant inhibition of cellular proliferation (p < 0.001) in the NCI-H226 cell line. We continue to assess this compound by other methodologies to confirm its potential utility in the treatment of MPM.
Conclusion:
KAT5, a lysine acetyltransferase associated with cisplatin resistance in cancer is significantly altered in MPM. A small molecule inhibitor of this protein shows significant anti-proliferative effects in MPM cell lines. Targeting this protein may have important future implications for the management of MPM.
