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H. Brahmbhatt

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    P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P1.01-072 - Targeted Delivery of a Synthetic microRNA-Based Mimic to Treat Thoracic Cancers (ID 2911)

      09:30 - 17:00  |  Author(s): H. Brahmbhatt

      • Abstract
      • Slides

      MicroRNA expression is commonly suppressed in cancer, contributing to tumor cell biology. Recently we demonstrated that multiple members of the miR-15/16 family are downregulated and have tumor suppressor functions in malignant pleural mesothelioma (MPM), an asbestos-related cancer for which few treatments are available. These results are similar to previous findings in non-small cell lung cancer (NSCLC). As multiple microRNAs from the same family are downregulated in MPM, we investigated whether a single synthetic mimic based on the consensus sequence of the entire family could restore activity of the entire family.

      Novel microRNA mimics based on the consensus sequence of the miR-15/107 group were designed (con15/107.1 to 4). The effects on growth, migration, target regulation, drug sensitivity and angiogenesis of the con15/107 mimics were compared with native miR-15 and miR-16 mimics using standard assays in MPM and lung cancer cell lines in vitro. The regulation of specific target genes was assessed by RT-qPCR, Western blot and luciferase reporter assays. Global gene regulation was assessed by proteomics. Activity of con15/107 mimics was investigated in vivo in xenograft models in nude mice.

      The consensus mimics inhibited growth and migration of MPM and lung cancer cell lines in vitro, and effects were greater than with native miR-15 or miR-16 mimics. Growth inhibition was associated with an induction of apoptosis, and downregulation of predicted targets of the mimics. Target gene interactions were confirmed with 3’UTR reporter constructs, and proteomics identified a number of candidate genes involved in consensus mimic-induced growth inhibition. Consensus mimics also sensitized multiple MPM and lung cancer cell lines to chemotherapy agents, and inhibited angiogenic activity in endothelial cells. In a xenograft model, the consensus mimic con15/107.2, packaged in bacterially-derived, EGFR antibody-targeted, EDV[TM]nanocells, inhibited MPM tumor growth in vivo.

      The novel con15/107 mimics based on the consensus sequence of the miR-15/107 group have greater activity than native miR-15 or miR-16 mimics in vitro and are active in vivo. Increased activity correlates to greater target gene downregulation. These preclinical studies support a Phase I clinical trial has been initiated for patients with MPM or NSCLC failing standard therapy. This represents the first trial of microRNA replacement as a therapy for thoracic cancer.

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