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James Chung-man Ho



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    P2.06 - Mesothelioma (Not CME Accredited Session) (ID 955)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.06-19 - Targeting Polyamines as Potential Adjuvant Therapy in Malignant Pleural Mesothelioma Xenograft Models (ID 13090)

      16:45 - 18:00  |  Author(s): James Chung-man Ho

      • Abstract
      • Slides

      Background

      Inhaling asbestos fibers is one of the commonest of malignant pleural mesothelioma (MPM). Although the import and use of asbestos have been restricted, the incidence of MPM is still rising due to a long lag time in malignant transformation. In 2004, the US Food and Drug Administration approved a combination of pemetrexed with cisplatin for treatment of unresectable MPM. At the same time, development of novel adjuvant therapeutic options for resected early-stage disease is also urgently needed. Ornithine decarboxylase (ODC) is highly expressed in 211H and H226 MPM xenografts and clinical tumor samples. Upregulation of ODC increases polyamine production and enhances tumor growth. a-difluoromethylornithine (DFMO) is a specific ODC inhibitor. Recent preclinical studies have demonstrated the adjuvant effect of DFMO in colon cancers using xenograft model. However, adjuvant effect of DFMO in MPM has not yet been studied. This study aims to disclose the adjuvant effect of DFMO in MPM xenograft models. The findings from this study will provide scientific foundation for future design of clinical trials of DFMO for adjuvant therapy in early disease for advanced MPM.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Nude mice were fed with DFMO in drinking water 7 days before subcutaneous inoculation of 200,000 tumor cells (211H (biphasic) or H226 (epithelioid)). Mice with tumor size >600mm3 were considered reaching humane endpoint. Spermidine levels, protein expression, cytokines concentrations, NFkB translocation and apoptosis were investigated by Dot plot, Western blot, ELISA, immunofluorescence staining and TUNEL assay respectively.

      4c3880bb027f159e801041b1021e88e8 Result

      DFMO suppressed tumor growth in both xenografts. DFMO increased median survival from 49.5 days in control arm to 65 days in treatment arm in mice with 211H xenografts (p = 0.08), while from 44 days to 120 days in those with H226 xenografts (p = 0.0002). In H226 xenograft model, 43% of treated mice have not yet reached humane endpoint, mimicking long-term survival. Upon DFMO treatment, decrease in spermidine level, increase in nitrotyrosine content, nuclear translocation of NFkB, elevation of serum IL-6 and activation of apoptosis were observed in both xenografts. In addition, increase in nitrocysteine level, decrease in serum keratinocyte chemoattractant (KC), increase in serum TNF alpha, elevation of DNA lesion and inhibition of Akt/mTOR pathway were induced by DFMO in H226 xenografts, which may explain higher potency of DFMO in this xenograft.

      8eea62084ca7e541d918e823422bd82e Conclusion

      DFMO may have a potential role as adjuvant therapy in MPM especially epithelioid mesothelioma.

      Acknowledgment: This research was supported by Hong Kong Pneumoconiosis Compensation Fund Board, HKSAR.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 978)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.12-08 - The Role of Contactin 1 on Acquired Resistance to Pegylated Arginase in Small Cell Lung Cancer (ID 13103)

      12:00 - 13:30  |  Author(s): James Chung-man Ho

      • Abstract
      • Slides

      Background

      Small cell lung cancer (SCLC) accounts for about 15% of all lung cancer cases. SCLC is characterized by easy to relapse, and current treatment lacks tumor specificity. Arginine is an important amino acid in human, but some tumors lose the ability to synthesize it. So arginine deprivation has become a targeted therapy in certain tumors. BCT-100 is a pegylated arginase with anticancer activity in arginine auxotrophic tumors, such as human melanoma, hepatocellular carcinoma and acute myeloid leukemia. Contactin 1 (CNTN1) is a cell adhesion molecule which plays an important role in drug resistance. The aim of this study is to determine the effects of CNTN1 on BCT-100 acquired resistance in SCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      BCT-100 resistant (BR) cells, H446-BR and H526-BR cells, were developed by incubating with serially increasing concentration of BCT-100 with parental H446 (adherent cell line) and H526 (suspension cell line) cells respectively. Gene chip assay was employed to fish out the potential targeted biomarkers in BR cell lines. MTT assay was used to detect cell viability on BR cell lines. Western blotting was employed to evaluate the protein expression. Knockdown of CNTN1 was performed using specific shRNA. Wound healing assay was used to evaluate the cell migration ability in H446 and H446-BR adherent cell lines. Flow cytometry was applied to detect the related biomarkers in BR cells.

      4c3880bb027f159e801041b1021e88e8 Result

      The protein expression of CNTN1 in H446-BR and H526-BR cells was 2.7 folds and 5.3 folds higher than that in parental cells respectively. Cell migration ability in BR cells was stronger than parental cells: wound healing rate was greatly increased from 48.5% to 69.9% in H446-BR cells. Epithelial-mesenchymal transition (EMT) progression and AKT activation were observed in both BR cell lines. Knockdown of CNTN1 re-sensitized BR cells to BCT-100 treatment and reversed the EMT progression via inhibiting AKT pathway.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Contactin 1 modulates BCT-100 resistance through induction of EMT by activating AKT pathway in SCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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