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Minju Kim2 1 4 So Jin Lee3 Sun Hwa Kim1 Thomas Roberts4 Ick Chan Kwon2 1

2, KU-KIST Graduate School of Converging Science and Technology, Seoul, , Korea (the Republic of)
1, Korea Institute of Science and Technology, Seoul, , Korea (the Republic of)
4, Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts, United States
3, Samyang Biopharmaceuticals, Seongnam-si, , Korea (the Republic of)

Cancer is an unconquered disease affecting millions of patients a year. To overcome the critical drawback of conventional therapies, targeted-therapy has gained attention as next generation strategy to cure cancer patients with less toxicity. Among many designs, biological material based nucleic acid as drug agent was demonstrated by numerous groups from early 2000s. Small interfering RNA, or siRNA, is non-coding short RNA molecules capable of regulating protein expression using RNA interference machinery. Utilizing siRNA as biological drug to repair cancerous metabolism caused by mutated protein has resulted in positive outcome with anti-cancer effects in pre-clinical experiments and clinical trials. In fact, siRNA therapeutics by Alnylam Pharmaceuticals is FDA-approved for clinical use for respiratory syncytial virus infections. However, the delivery of siRNA has been major hurdle in translating the efficacy in various cancer patients. Here, we incorporated nanoparticle to enhance the delivery of siRNA to target tumor sites under systemic administration. Bio-compatible and bio-degradable glycol chitosan was self-assembled with polymerized siRNA to form stable delivery complex to tumor sites to downregulate oncogenic expression. Phosphoinositide 3-kinase (Pi3K) and Ras are the most commonly activated oncogenic pathways in solid malignancies and have interdependent relationship via feedback loop system. Many previous reports have shown that dual-inhibition of Pi3K and Ras pathway has therapeutic effects in various cancer models. Though use of multi-drug achieves simultaneous inhibition of specific pathways, undesired side-effects and resistance occasionally occur from collision of pharmacokinetics of small molecule inhibitors. In addition, currently none of Ras inhibitor is potent enough for pathway inhibition, instead secondary inhibitor on downstream protein, MEK, is more commonly used. Here, we used siRNA therapeutics in collaboration with pan-Pi3k inhibitor to demonstrate anti-tumor effects in ovarian cancer. Ovarian cancer cell line with PTEN deficiency and KrasG12D mutation were obtained from spontaneous tumor model to examine synergistic effect of Pi3k and Ras inhibition. In cellular level, GDC and siKRAS impeded the activity of Pi3k activity and expression of Ras, respectively. When both pathways were simultaneously inhibited, cell proliferation and migration significantly delayed. In allograft ovarian cancer model, tumor sizes were critically reduced when both Pi3k and Ras were inhibited together. The immunoblot and immunohistochemistry results verified that that dual-inhibition impeded tumor growth and induced apoptosis. Here, we demonstrate that combination inhibition of Pi3k and Ras using different treatment strategies is an exceeding alternative over conventional single-agent treatments.

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