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M. Williams
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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
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-072 - Targeted Delivery of a Synthetic microRNA-Based Mimic to Treat Thoracic Cancers (ID 2911)
09:30 - 09:30 | Author(s): M. Williams
- Abstract
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
