Development of miR-27a* for the Treatment of Head and Neck Squamous Cell Carcinoma

PROJECT SUMMARY Overexpression of epidermal growth factor receptor (EGFR), which frequently occurs in head and neck squamous cell carcinoma (HNSCC), correlates with poor patient survival. However, therapies targeting EGFR in multimodality therapy for HNSCC have not significantly improved outcomes for advanced stage disease. Therefore, alternative approaches targeting EGFR and associated critical pathways are needed to combat HNSCC, the sixth most diagnosed cancer worldwide. Our previous research identified microRNA-27a* (miR- 27a*; miR-27a-5p) as a regulator of EGFR, protein kinase B (AKT1), and mammalian target of rapamycin (mTOR). All these proteins are commonly upregulated in cancer cells, likely as a consequence of tumors repressing miR-27a* expression, and provide a cell survival advantage. Furthermore, re-introduction of miR- 27a* into tumor cells in vitro and in vivo causes apoptosis, raising the exciting prospect that by simultaneously targeting multiple oncogenic pathways, miR-27a* may be an effective therapy for HNSCC. Accordingly, our long-term clinical translational objective is to develop miR-27a* as an effective multimodality therapeutic option for HNSCC, which is directly relevant to the mission of the NIDCR “…to improve oral, dental, and craniofacial health through research...”. This requires us to understand the functional role of miR-27a* targets, to define novel therapeutic combinations that enhance the ability of miR-27a* to inhibit HNSCC progression, and to develop an approach to translate miR-27a* into the clinical arena. Currently, a knowledge gap exists regarding validated targets of miR-27a* and the pathways they influence in HNSCC progression, as well as combinatorial treatments that could augment miR-27a* anti-tumor effects. Moreover, methods for tumor-specific delivery of miRs are lacking. Accordingly, we will comprehensively test the potential of miR-27a* in conjunction with established and novel combinatorial agents for HNSCC treatment using in vitro and orthotopic in vivo tumor models. To overcome challenges in the delivery of miRs in vivo, we will use a novel ultrasound-targeted microbubble delivery platform to administer miR-27a* specifically to tumor. The overall objective of this proposal is to determine the role of miR-27a* in modulating biological processes through regulation of its target genes, while leveraging these and previous findings towards the therapeutic use of miR-27a* within the context of current standard of care and future combinatorial treatment regimens. Our central hypothesis is that re- introduction of miR-27a* in HNSCC negatively modulates critical oncogenic drivers to promote tumor apoptosis. We propose three Specific Aims: (1) To confirm direct molecular targets of miR-27a* that mediate HNSCC pathogenesis; (2) To define miR-27a*-combinatorial treatment regimens for HNSCC; and (3) To characterize the role of miR-27a* delivery in enhancing current and future multimodality treatment regimens for HNSCC. The findings will significantly impact our understanding of miR-27a* targets, the processes they regulate, their role in tumor progression, and ultimately inform clinical implementation of miR-27a* therapy.