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A. Nakas



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    P1.01 - Poster Session 1 - Cancer Biology (ID 143)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.01-026 - Pro-tumorigenic alteration of signalling pathways in normal mesothelium: Contribution of non-mesothelial cells in malignant mesothelioma carcinogenesis (ID 1587)

      09:30 - 16:30  |  Author(s): A. Nakas

      • Abstract

      Background
      Malignant mesothelioma (MM) is an aggressive, fatal tumour of the pleura or peritoneum and strongly related to asbestos exposure. Malignant pleural mesothelioma (MPM) is the most common and occurs with a latency of up to 40 years. The mechanism of MM carcinogenesis is not well understood and the heterogeneity of the tumour is considered to be a major barrier to successful therapy. Several studies have identified changes in the expression and activities of defined cell signalling pathways in mesothelial and stromal cells, but the relationship between different cell types in the process of tumorigenesis has not been studied.

      Methods
      To examine the pro-oncogenic role(s) of different cell populations, the effect of primary fibroblasts from human mesotheliomas and activated macrophages on cellular signalling in normal untransformed mesothelial cells was monitored using imaging and immunoblotting techniques.

      Results
      Although the subcellular location of damage-associated molecular pattern (DAMP) protein HMGB1 remained nuclear in normal mesothelial cells co-cultured or treated with conditioned medium, the activation levels of growth modulating signalling pathways were altered in these cells. The proliferation and migration rates of normal mesothelial cells were also affected by paracrine signalling from activated fibroblasts and macrophages.

      Conclusion
      Thus, non-mesothelial cells instigate alterations in cellular signalling in mesothelial cells. Further integral examination of the aberrant signalling pathways, especially at early stages of neoplasia, will provide new insights into the mechanisms underlying malignant mesothelioma carcinogenesis.

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    P3.05 - Poster Session 3 - Preclinical Models of Therapeutics/Imaging (ID 159)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.05-009 - Metabolic Reprogramming Overcomes Resistance to ABT-737 -induced Apoptosis in Pre-clinical Models of Malignant Pleural Mesothelioma (ID 1963)

      09:30 - 16:30  |  Author(s): A. Nakas

      • Abstract

      Background
      Malignant mesothelioma (MM) is an aggressive, fatal, tumour of the pleura or peritoneum and is strongly related to asbestos exposure. Clinically, there is no curative therapy for MM and the profound chemoresistance of MM is well documented, reportedly being due to the ability of MM cells to escape cell death. Unravelling the molecular mechanisms employed by MM cells to evade cell death will therefore provide new insights into key cell death pathways that may be targeted for successful therapy. Currently, the Bcl-2 repertoire is an undervalued and attractive pharmacological target for mesothelioma therapy. The aims of this study were to investigate the sensitivity of MM to the BH3-mimetic, ABT-737, and identify mechanisms of overcoming resistance to support personalized therapy.

      Methods
      Sensitivity to the highly selective BCL-2/BCL-XL antagonist, ABT-737, was investigated using FACs-based analysis and immunoblotting techniques in a panel of MM cell lines and tumour cells isolated from freshly resected MM tumours. In addition, patient-derived tumour explants were similarly analysed, providing a clinically relevant 3D mesothelioma model. Furthermore, to explore the possibility that tumour cell metabolism may modulate the sensitivity of MM cells to ABT-737, we investigated the effect of inhibiting glycolysis with 2-deoxyglucose (2-DG) on ABT-737 -induced apoptosis in relevant pre-clinical models of MM.

      Results
      The majority of MM cell lines and freshly-derived cultured tumour cells were resistant to ABT-737, suggesting a deregulation of cell death signalling at the level of mitochondria. Aerobic glycolysis (Warburg effect) is a process by which tumour cells gain not only growth advantage (providing much needed “building blocks”) but also an increased survival potential. Importantly we report that, in MM, glycolysis can be inhibited by 2-deoxyglucose(2-DG), a competitive inhibitor of hexokinase. Although exposure to 2-DG did not induce cell death, 2-DG induced a time- and concentration-dependent potentiation of ABT-737 -induced apoptosis in either established mesothelioma cell lines or newly-derived tumour cells from patients. BCL-2-family member profiling revealed that, while the predominant pro-survival members expressed in MM were MCL-1 and BCL-XL, 2-DG selectively decreased MCL-1 protein levels, a leading cause of resistance to ABT-737 in other tumour models.

      Conclusion
      High constitutive levels of MCL-1 most likely explain the inherent resistance of MM cells to the highly selective BCL-2/BCL-XL antagonist, ABT-737. Importantly, 2-DG-dependent down-regulation of MCL-1 provides a potential mechanism for overcoming resistance to ABT-737 in the clinical setting.