Decaens, Thomas;
Factor, Valentina M.;
Kulic, Iva;
Andersen, Jesper B.;
Seo, Daekwan;
Lee, Yun-Han;
Judge, Adam D.;
Conner, Elizabeth A.;
MacLachlan, Ian;
Thorgeirsson, Snorri S.
Abstract 5661: Nanoparticle based combinatorial siRNA therapy against human hepatocellular carcinoma (HCC)
Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>Background: We have previously demonstrated the therapeutic effect of lipid nanoparticles (LNP) loaded with single siRNA targeting CSN5 and WEE1 against human HCC in mouse models.</jats:p>
<jats:p>Aim: To test the benefit of a combinatorial versus single siRNA therapy in mouse models of human HCC and to identify molecular mechanism(s) involved in therapeutic response by extensive microarray analyses.</jats:p>
<jats:p>Materials and Methods: LNP formulations of chemically modified siRNAs targeting CSN5 and WEE1 were produced by Tekmira® Pharmaceuticals. SCID-beige mice were used for subcutaneous (Hep3B) and intra-hepatic (Huh7-luciferase) tumor transplantation. Mice with established tumors were treated intravenously with 4 mg/kg single agent siRNA or 2 mg/kg + 2 mg/kg siCSN5:siWEE1 siRNA co-encapsulated in the same LNP. Tumors were assayed following 1 to 9 injected doses. Tumor progression in the Huh7 orthotopic model was monitored by bioluminescence imaging and metastases were evaluated at endpoint.</jats:p>
<jats:p>Results: Significant target silencing was observed in tumors after single or repeat administration with no antagonism between siRNAs occurring in the CSN5:WEE1 combination. We observed significant inhibition of tumor growth and metastases in mice treated with active siRNAs compared to LNP containing a non-targeting control sequence. Potency was not lost with siCSN5:siWEE1 LNP, where the concentration of each siRNA is halved in combination, relative to the most efficacious single agent. Data from preliminary microarray analyses demonstrate a strong transcriptome difference between each treatment group.</jats:p>
<jats:p>Conclusion: We demonstrate a clear efficacy of a LNP based combinatorial siRNA therapy in human mouse models of HCC. Overall this therapy led to a significant decrease of tumor size induced by mRNA inhibition</jats:p>
<jats:p>Citation Format: Thomas Decaens, Valentina M. Factor, Iva Kulic, Jesper B. Andersen, Daekwan Seo, Yun-Han Lee, Adam D. Judge, Elizabeth A. Conner, Ian MacLachlan, Snorri S. Thorgeirsson. Nanoparticle based combinatorial siRNA therapy against human hepatocellular carcinoma (HCC) . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5661. doi:10.1158/1538-7445.AM2013-5661</jats:p>