A novel miR-198 replacement therapy for pancreatic cancer

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DESCRIPTION (provided by applicant): We recently discovered a tumorigenic factor interactome connected through the tumor suppressor microRNA-198 in human pancreatic cancer (PC) patient samples and confirmed the tumor suppressive roles of miR-198 in PC animal models. We found that miR-198 is downregulated in PC and is involved in an intricate reciprocal regulatory loop with mesothelin (MSLN), which represses miR-198 through NF-kB-mediated homeobox transcription factor POU2F2 (OCT-2) induction. Furthermore, miR-198 repression leads to overexpression of pre-B-cell leukemia homeobox factor 1 (PBX-1) and valosin-containing protein (VCP). The dysregulated PBX-1/VCP axis leads to an increase in tumorigenicity. Reconstitution of miR-198 in PC cells results in reduced tumor growth, decreased metastasis, and increased survival through direct targeting of MSLN, PBX-1, and VCP. Our preliminary data strongly suggest the significant role of miR-198 and this interactome in PC pathogenesis. In addition, we found that miR-198 can sensitize PC cells for gemcitabine killing because miR-198 effectively downregulates VCP expression and inhibits autophagy maturation in PC cells. In this proposal, we hypothesize that miR-198 and this interactome could serve as a potential prognostic marker and the miR-198 replacement therapy could attack this tumorigenic network through a central vantage point and improve therapeutic efficacy in pre-clinical animal models. Three specific aims are proposed: 1). Demonstrate the significant role of miR-198 and the tumorigenic factor interactome in human PC clinical prognosis in a large cohort of PC patient samples; 2). Design and characterize MSLN-specific targeted miR-198 nanoparticles for specifically delivering miR-198 to PC cells; and 3). Demonstrate the therapeutic efficacy of MSLN-targeted miR-198 replacement in PC patient-derived xenograft (PDX) mouse models. The project will substantially contribute to PC research and will have an enormous impact on clinical practice for patients with PC.