Author of

• 31105

  +

  P2.06 - Mesothelioma (ID 170)

  • Event: WCLC 2019
  • Type: Poster Viewing in the Exhibit Hall
  • Track: Mesothelioma
  • Presentations: 1
  • Now Available
  • Moderators:
  • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall

  • 31123

    +

    P2.06-18 - Targeting Polyamines for Treatment of Malignant Pleural Mesothelioma in Xenograft Models (Now Available) (ID 516)

    10:15 - 18:15  |  Author(s): Sheng Yan
    • Abstract
    • Slides

    Background
    

    Inhaling asbestos fibers is the commonest cause 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. However, overall prognosis is still extremely poor. As such, development of novel therapeutic options is 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 which can suppress polyamines production. Recent preclinical studies have demonstrated the therapeutic effect of DFMO in colon cancers using xenograft model. However, therapeutic effect of DFMO in MPM has not yet been studied. This study aims to disclose the therapeutic 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 therapy for advanced MPM.

    Method
    

    Nude mice were subcutaneous inoculated with tumor cells [211H (biphasic) or H226 (epithelioid)]. Mice were treated with DFMO in drinking water when tumor size reached 50-100 mm³. Mice with tumor size >600mm³ were considered reaching humane endpoint. Spermidine levels, protein expression, cytokines concentrations and apoptosis were investigated by Dot plot, Western blot, ELISA and TUNEL assay respectively.

    Result
    

    DFMO suppressed tumor growth in both xenografts. DFMO increased median survival from 29 days in control arm to 41 days in treatment arm in mice with 211H xenografts (p = 0.0234), while from 30 days to 43.5 days in those with H226 xenografts (p = 0.0050). There was no synergism when combining DFMO (0.5% or 2%) with either cisplatin (1.25 or 2.5 mg/kg) or pemetrexed (75 or 150 mg/kg). The tumor suppressive effect of DFMO was more effective when compared with cisplatin or pemetrexed. Upon DFMO treatment, decrease in spermidine level, increase in nitrotyrosine content, and activation of apoptosis were observed in both xenografts. In addition, increase in nitrosocysteine level, increase in intratumoral IL-6, keratinocyte chemoattractant (KC) and TNF alpha as well as elevation of DNA lesion and downregulation of pAkt were induced by DFMO in H226 xenografts.

    Conclusion
    

    DFMO may have a potential role in treating MPM.

    Acknowledgment: This research was supported by Hong Kong Pneumoconiosis Compensation Fund Board, HKSAR and YC Chan Scientist Award.

    Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.