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A. Baird
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-088 - Lung Cancer Cells Can Alter the Behaviour of Normal Bronchial Epithelial Cells Through Multiple Mechanisms (ID 1312)
09:30 - 09:30 | Author(s): A. Baird
- Abstract
Background:
Lung cancer is one of the most heterogeneous of all solid cancers. This may in part be due to hi-jacking and additional bystander affects that are exerted on the normal lung cell population by the cancer cells. A number of pathways may be stimulated through soluble factors or effector filled vesicles such as exosomes secreted by cancer cells. The aim of this project was to evaluate the effects of non-small cell lung cancer (NSCLC) cells on an immortalised normal bronchial epithelial cell line.
Methods:
A normal bronchial epithelial cell line (HBEC4) was exposed to adenocarcinoma, large cell and squamous NSCLC cell lines and a number of phenotypic and genotypic characterisations were undertaken. These included cellular proliferation (BrdU ELISA), gene (RT-PCR) and miRNA expression screening (Nanostring). The effect of cancer exosome fractions was also determined.
Results:
Exposure to various subtypes of NSCLC significantly increased the cellular proliferation rate of the immortalised cell line in a number of models. Expression of a number of miRNAs were altered in the normal cells pre- and post exposure to the cancer cells. Various stem cell factor markers (KLF4, Oct, c-myc) were also significantly changed at the mRNA level. In addition, exosome fractions altered the behaviour of the normal cell line, likewise stimulating cell proliferation.
Conclusion:
Lung cancer cells may influence normal cell behaviour in both a direct and indirect manner using multiple mechanisms. Normal bronchial epithelial cells with stem like features may be induced to proliferate and behave in a malignant manner. This, akin to Hodgkin’s lymphoma, may contribute significantly to the composition of the tumour. Furthermore this observation may contribute to the heterogeneity of lung cancer tumours and affect treatment response. Ongoing studies are evaluating these effects in novel 2D and 3D culture systems.
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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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P1.08-014 - The Small Molecule Inhibitor, LCRF004, Is Effective in Targeting the RON/MST1R Pathway in Malignant Pleural Mesothelioma (ID 1311)
09:30 - 09:30 | Author(s): A. Baird
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer. We have previously identified RON as frequently activated in MPM patient samples and cell lines. RON is a member of the MET proto-oncogene family and is bound by macrophage stimulating protein (MSP). High positivity for total RON by IHC was an independent predictor of favourable prognosis. Additionally, elevated expression levels of MSP correlated with better survival. The aim of this study was to further examine the MSP-RON signalling axis in MPM using a RON inhibitor, LCRF004.
Methods:
MPM cell lines and a normal mesothelial cell line were screened for the expression of RON and MSP at the protein (Western) and mRNA (RT-PCR) level. Downstream mediators affected by MSP stimulation and LCRF004 were identified using a proteome profiler array. The effect of LCRF004 and MSP were examined using proliferation (BrdU ELISA), viability (High Content Analysis), migration (xCELLigence), apoptosis and cell cycle (HCA) assays. A xenograft study was also completed.
Results:
Treatment with LCRF004 resulted in a significant decrease in proliferation, viability and migration in vitro and reduced tumour growth in vivo (p<0.05, compared with vehicle control). In addition, LCRF004 significantly increased apoptosis. In terms of cell cycle, drug treatment decreased cells in 2n, whilst increasing cells in the G0/G1 phase. Experiments are on going to further characterise the mechanism of action of LCRF004.
Conclusion:
The in vivo and in vitro data generated in this study, indicates that the MSP-RON signalling axis is a potential target in MPM. Targeting the RTK domain of the RON receptor with a small molecule inhibitor is an effective interventional strategy in MPM.
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-102 - Targeting Inflammatory Mediators to Overcome Intrinsic and Acquired Cisplatin Resistance in Non-Small Cell Lung Cancer (ID 1314)
09:30 - 09:30 | Author(s): A. Baird
- Abstract
Background:
Cisplatin based doublet-chemotherapy is commonly used in non-small cell lung cancer (NSCLC) treatment with an initial objective response rate of 40-50%. However, intrinsic and acquired chemo-resistance constitutes a major clinical obstacle. The mechanisms of resistance have yet to be fully understood. We have previously demonstrated that NF-κB levels are elevated in cisplatin resistant cells (CisR) and that the use of an NF-κB inhibitor, DHMEQ, resulted in greater CisR cell death. The goal of this project is to elucidate the mechanistic links between NF-κB regulated pathways and the development of cisplatin resistant NSCLC.
Methods:
The expression of NF-κB mediators and immune regulators were assessed in an isogenic NSCLC cell line model of cisplatin resistance using qPCR arrays (252 genes). A number of targets were identified and validated using PCR. The effect of drug combinations (Cisplatin and DHMEQ) was also determined. Comet assays (DNA damage) were also performed to determine the effect of DHMEQ alone or in combination with irradiation (6 Gy).
Results:
Various chemokines and their receptors were elevated in cisplatin resistant (CisR) cells compared with cisplatin sensitive (PT). In addition, a number of key TLRs and regulators of the innate immune pathway were altered. DHMEQ enhanced cellular sensitivity to cisplatin in both PT and CisR cell lines (p<0.05). This drug also overcame the chemo-protective effect of a number of chemokines and enhanced irradiation induced DNA damage. An animal study will commence shortly using DHMEQ alone and in combination with cisplatin.
Conclusion:
Immune-modulators such as DHMEQ may be a novel viable option in addressing inflammatory mediated acquired and intrinsic NSCLC chemo-resistance. In addition, immune regulators identified in this project may provide innovative targets for immuno-oncology therapy.
