Abstract PR5: Treatment of ovarian cancer with targeted tumor-penetrating siRNA nanocomplexes

Abstract Whole-genome analysis of cancer samples is identifying many potential therapeutic targets, by virtue of their being frequently mutated or functionally essential in specific types of cancer. However, we lack efficient ways to test the therapeutic benefit of modulating targets in vivo. RNAi offers one potential solution; however, approaches to deliver siRNA in vivo have been challenging due to their susceptibility to serum nucleases, endosomal entrapment, and stimulation of innate immunity. Furthermore, nanoparticle- and antibody-based siRNA delivery approaches have historically suffered from limited tumor penetration and low transvascular transit, thereby limiting the applicability of parenchymal siRNA targets. Here we describe a tumor penetrating nanocomplex (TPN) comprised of siRNA complexed to a tandem tumor-penetrating and membrane-translocating peptide, which enables the homing of siRNA deep into tumor parenchyma. Upon complexation with siRNA, the resulting nanocomplex is stable, non-immunostimulatory, displays homing peptides in a multivalent fashion that increases their binding avidity and delivers siRNA to the cytosol of tumor cells through receptor-specific interactions and membrane translocation. Upon systemic administration into mice, this nanocomplex penetrates into the parenchyma of metastatic peritoneal tumors and silences target genes in cells of interest in a receptor-specific manner. We employed TPNs in vivo to evaluate ID4, a novel candidate oncogene in ovarian cancer, which we identified by combining genome-scale RNAi screening of cancer cell lines with genome-scale sequence analysis of patient tumors. We show that treatment of tumor-bearing mice with ID4-specific TPNs suppresses tumor growth and significantly improved survival. These findings provide a framework for the identification, credentialing, and understanding of novel cancer targets as well as validating a specific therapeutic target in ovarian cancer. This abstract is also presented as Poster B2. Citation Format: Yin Ren, Hiu Wing Cheung, Ronny Drapkin, David Root, Justin Lo, Valentina Fogal, Erkki Ruoslahti, William Hahn, Sangeeta Bhatia, Geoffrey von Maltzahn, Amit Agrawal, Glenn Cowley, Barbara Weir, Jesse Boehm, Pablo Tamayo, Jill Mesirov, Alison Karst. Treatment of ovarian cancer with targeted tumor-penetrating siRNA nanocomplexes [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr PR5.