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Roma Pahwa



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    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
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      P2.06-13 - Targeting RAS Signaling in Malignant Mesothelioma  (Now Available) (ID 652)

      10:15 - 18:15  |  Author(s): Roma Pahwa

      • Abstract
      • Slides

      Background

      Malignant pleural mesothelioma (MPM) is distinguished by molecular features, such as activated and redundant multiple tyrosine kinases signaling via the Ras pathways. Several pharmacologic strategies have been attempted to disrupt this pathogenic axis, but clinically effective agents remain elusive. We propose to leverage microRNA (miRNA) as a potential therapeutic approach, since miRNA can coherently regulate multiple simultaneous gene targets that comprise critical biologic networks.

      Method

      Our prior miRNA profiling results of human MPM (GSE40345) were cross-referenced with TCGA-Meso data to identify prognostic miRNAs. Both MPM cell lines and tissues (tumors and normal pleura) were assessed using quantitative and functional biologic assays that revealed specific molecular mechanisms of relevant miRNA. In silico algorithms identified downstream gene targets that were verified by 3’-UTR luciferase assay. Murine models of MPM xenografts were used to verify in vitro observations of miRNA effects. Kaplan-Meier assessed outcomes in vivo.

      Result

      Our analyses showed underexpression of miR-206 by 12-fold in MPM tumors compared to normal pleura. TCGA data (n=74 MPM) indicated worse survival in patients with low miR-206 (25-fold decrease) compared to higher miR-206 expression. We confirmed that miR-206 was significantly underexpressed by qRT-PCR analysis of new, randomly selected MPM tumors versus normal pleurae tissues. In MPM cell lines, ectopic re-expression of miR-206 dramatically suppressed cell proliferation, invasiveness, and growth in soft-agar. Interestingly, we noted several MPM-prognostic genes (p<0.05) regulated by miR-206: KRAS, CDK4, CCND1, and IGF1R. This signaling axis of KRAS/CDK4/CCND1 is important in MPM as it summates well-known dysregulated tyrosine kinase receptors (EGF, IGF-1, VEGF, MET, etc) that are upstream. The KRAS/CDK4/CCND1 axis is associated with cell cycle progression and survival of cancer cells, but is not an easily druggable target. In vitro, miR-206 treatment significantly downregulated KRAS, CDK4 and CCND1 as well upstream target genes such as MET, EGFR, IGF1R and VEGFA. In vivo, miR-206 treatment significantly suppressed MPM tumor growth in subcutaneous and orthotopic xenograft models compared to control. Kaplan-Meier analysis showed that miR-206 treatment improved overall survival.

      Conclusion

      miR-206 exerts tumor suppressive effects in MPM via inhibition of KRAS/CDK4/CCND1 signaling, which mimics simultaneous blocking of multiple tyrosine kinases. Loss of miR-206 and concomitant overexpression of KRAS, CDK4 and CCND1 formed a novel poor prognosis signature in MPM. Our results indicate that miR-206 is a rational agent to be developed further in preclinical MPM models as a promising therapeutic.

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