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L. Macdonagh
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P1.09 - Mesothelioma (ID 695)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Mesothelioma
- Presentations: 2
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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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): L. Macdonagh
- 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.
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P1.09-007 - Targeting MET/TAM Receptors in Mesothelioma: Are Multi-TKIs Superior to Specific TKI? (ID 9959)
09:30 - 09:30 | Author(s): L. Macdonagh
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer associated with exposure to asbestos, and most patients die within 24 months of diagnosis. There is an urgent need to identify new therapies for treating MPM patients. Targeting “addicted” receptor tyrosine kinase (RTK) signalling networks has become a critical therapy option in cancer therapy. RTK hetero-dimerization may however, be a key element in the development of resistance to such therapy. As such Tyrosine kinase inhibitors (TKIs) with the ability to target multiple receptors may have superior efficacy to those targeting individual receptors. We and others have identified c-MET, MST1R (also known as RON), Axl and Tyro3 as RTKs frequently overexpressed and activated in MPM, making these attractive candidate targets. Several agents have been developed which target these. LCRF0004 specifically targets MST1R, whereas BMS-777607, RXDX-106 or Merestinib (LY2801653) are orally bioavailable small molecule inhibitors which inhibit c-MET, MST1R, Axl and Tyro3 at nM concentrations. These drugs may therefore have clinical utility in the treatment/management of MPM.
Method:
Expression of RON/MET/TAM and associated ligands were assessed in a cohort of patient samples and MPM cell lines comprising benign, epithelial, biphasic, and sarcomatoid histologies. In vitro and in vivo experiments were undertaken to determine the efficacy of single and multi RTK targeting agents (LCRF0004, RXDX-106, BMS-777607). The effects of LCRF0004 and BMS-777607 were subsequently examined in an in vivo SQ xenograft tumour model.
Result:
mRNA expression of the RON/MET/TAM family and associated ligands (MSP, GAS6) was detected in a large panel of normal pleural and MPM cell lines. In a cohort of patient samples, mRNA levels of c-MET, Axl, Tyro3 and various isoforms of MST1R (flRON, sfRON, t-ΔRON) and MSP but not Gas6 or MERTK were increased in tumours compared with benign pleural samples (p<0.05). No MET Exon 14 skipping mutations were detected. RTK targeting agents displayed in vitro efficacy in terms of reduced proliferation. In vivo, the multi-target TKI (BMS-777607) demonstrated superior anti-tumour activity compared with LCRF0004 (MST1R specific compound). IHC analysis of the xenograft tumours showed high cytoplasmic expression of Vimentin, Cytokeratin and Calretinin, with significant necrosis in many.
Conclusion:
Our data suggests that a multi-TKI, targeting the RON/MET/TAM signalling network, is superior to selective RTK inhibition as an interventional strategy in MPM.
