Author of

• 10557

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  P1.05 - Poster Session 1 - Preclinical Models of Therapeutics/Imaging (ID 156)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 10577

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    P1.05-020 - Identifying therapeutic targets for mesothelioma using siRNA (ID 3200)

    09:30 - 09:30  |  Author(s): C. Robinson
    • Abstract

    Background
    Mesothelioma is essentially incurable and new drugs to effectively treat it are urgently needed. Our strategy to achieve this aim was to identify candidate mouse and human genes that may have a role in mesothelioma growth and to inhibit their expression in fully transformed mesothelioma cell lines using siRNA.

    Methods
    The initial selection of candidate genes was made on the basis of their differential expression in transcriptome or CGH analyses when comparing malignant to normal mesothelial cells. This was combined with known functional information relevant to tumorigenesis. We also selected a small number of candidates from other published studies. A second set of candidates was chosen from expressed kinases with the idea that these genes are more likely to represent druggable targets given the broad range of kinase inhibitors that are widely available. Where possible, we identified mouse and human homologues of the 40 candidates and then generated both mouse and human siRNA libraries. We tested the effect of gene knockdown on the growth of mouse and human mesothelioma cell lines in vitro.

    Results
    We found knockdown was efficient and inhibition of a subset of the selected genes slowed cell growth significantly across a range of cell lines in both mouse and human systems. There was not complete concordance between the mouse and human: Incenp, Plk1 and Tpx2 were important pathways for murine cellular proliferation; whereas, AURKA, TPX2 and BIRC5 were relevant for human cellular proliferation only. KIF11 was identified in both studies.

    Conclusion
    These genes all have a function in chromosome positioning, centrosome separation and spindle assembly during cell mitosis. Our data show that targeting these gene products in mesothelioma cell line causes growth inhibition both in vitro and in vivo. These studies could provide new leads for drug development.

• 11515

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  P2.05 - Poster Session 2 - Preclinical Models of Therapeutics/Imaging (ID 158)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 11536

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    P2.05-021 - Molecular analysis of asbestos-induced mesotheliomas from SV40 TAg transgenic mice shows that they are highly concordant with human mesothelioma (ID 3211)

    09:30 - 09:30  |  Author(s): C. Robinson
    • Abstract

    Background
    Asbestos-induced mesothelioma in MexTAg transgenic mice closely resembles the key features of human disease. This model is highly suited to testing new chemotherapies and cancer prevention strategies. The resultant mesothelioma responds to cytotoxic chemotherapy with efficacy of the same order of responsiveness as human mesothelioma. The transgene, large T Antigen is an oncogene encoded by Simian Virus 40, and the role of this viral oncogene in tumourigenesis has been widely studied. Here we investigate the gene expression differences between TAg tumours and wild type tumours and examine overall similarity to human mesothelioma at the molecular level.

    Methods
    not applicable

    Results
    We found TAg expressing mouse tumours were 90% identical to wild type mouse tumours. The key pathway that was affected by these gene differences was cell cycle. Gene set enrichment analysis showed that the TAg:wild type tumour differences were homolgous to the Rb null genotype in a TAg dose dependent manner. To address whether transgenic mouse tumours were a good representation of human mesothelioma when compared to wild type mouse tumours, we showed that of genes differentially expressed between i) TAg or ii) wild type mouse tumours and mouse mesothelial cells, there were the same number of gene similarities with the set of genes that differentiate between human mesothelioma and human mesothelial cells. Human mesotheliomas commonly have a deletion of the cdkN2 locus, encoding the tumour suppressor genes p16 and p15. We found that while wild type mouse tumours contained the p16 deletion, TAg tumours did not.

    Conclusion
    In summary, the asbestos-induced mesotheliomas in MexTAg mice are comparable to human mesothelioma at the molecular level. We hypothesize that TAg expressing mice develop tumours in a more uniform way than wild type mice following asbestos exposure and are not dependent on deletion of p16 for tumourigenesis.

• 12418

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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
  • Moderators:
  • Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 12437

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    P3.05-020 - Strategies for the prevention of mesothelioma in MexTAg mice (ID 3205)

    09:30 - 09:30  |  Author(s): C. Robinson
    • Abstract

    Background
    Current treatments for mesothelioma typically increase median survival by a matter of months. Progress in treatment has been hampered by lack of a suitable small animal model, which could guide clinical advances, given limited numbers of patients eligible for clinical trials. To this end we recently developed a transgenic mouse model of mesothelioma in which the viral oncogene, SV40TAg (TAg) is directed to mesothelial cells by use of the cell type specific mesothelin promoter. MexTAg mice develop mesothelioma rapidly and uniformly, but only following exposure to the natural carcinogen, asbestos. The model closely mimics the human disease and is thus ideal for both rapid analysis of novel therapeutic studies and for investigating factors that might act synergistically with asbestos to cause disease. Since all MexTAg mice develop mesothelioma following asbestos exposure the model is highly suitable for early intervention and cancer prevention studies. An effective cancer prevention strategy for the millions of people who have been exposed to asbestos could have enormous benefit worldwide. Epidemiological evidence indicates that supplementation with some dietary factors or use of common drugs such as statins and non-steroidal anti-inflammatory drugs is associated with a lower incidence of cancer.

    Methods
    not applicable

    Results
    We previously reported that dietary supplementation with a number of antioxidants did not alter the time to develop disease nor overall survival, despite the widely accepted hypothesis that asbestos catalyzed production of reactive oxygen and nitrogen species contribute to the development of this cancer. We have extended these studies to test whether vitamin D, non-steroidal anti-inflammatories, statins and some other candidate diets could alter the pattern of disease in the MexTAg model. Supplemented diets were provided at levels based on published data and began 2 weeks prior to asbestos exposure in order to maximize our chance of detecting a benefit. Preliminary data suggests a single agent or nutraceutical may not be enough to prevent the multiple pathways involved in tumorigenesis. This is somewhat supported by epidemiological data from the Wittenoom cohort of asbestos exposed workers and residents.

    Conclusion
    In conclusion, we think it is unlikely that antioxidants, anti-inflammatories or other nutrient-specific dietary supplements will moderate the rate of mesothelioma in asbestos exposed populations.