Preclinical analysis of targeting miR-182 against melanoma liver metastasis.

Abstract

8554 Background: Malignant melanoma is a devastating cancer and the overall survival is extremely poor for stage IV disease. The paucity of effective treatments clearly illustrates the dire need of alternative therapies for metastatic melanoma. Targeting oncogenic microRNAs has the potential to become an important strategy for targeted therapy. Studies from our lab have demonstrated a prometastatic role for miR-182 in melanoma. Moreover, we proved that miR-182 repression in vitro impairs the invasive capacity of melanoma cells and triggers an antiproliferative response. Thus, we hypothesized that the silencing of miR-182 can be of therapeutic benefit in melanoma. Methods: We have tested the effect of anti-miR- 182 oligonucleotides synthesized with a phosphorothioate backbone in a mouse model of liver metastasis after intrasplenic injection of melanoma cells. 1E04 A375 cells stably transduced with the luciferase cDNA were injected into the spleen of NOD/Scid/IL2gR-/- (NOG) mice. Thirty mice received intrasplenic injections of A375 cells, and then were distributed into two groups to either receive anti-miR-182 or a control anti-miR (25 mg/Kg), administered by intraperitoneal injection twice weekly. Mice were monitored using in vivo fluorescence imaging for tumor cell migration from the spleen into the liver. Results: Luciferase imaging performed 4 weeks post-injection showed that mice treated with anti-miR-182 had an appreciably lower burden of macroscopic liver metastases compared to the control. Treatment with anti-miR-182 reduced the number of mice with > 50 macroscopic liver metastases by half. We also confirmed that the anti-miR treated cohort displays lower levels of miR-182 compared to the scrambled treated cohort both in the tumor tissue and in the liver parenchyma. Moroever, we demonstrated that miR-182 targets ADCY6 and FOXO3 were up-regulated in the tumor cells of anti- miR-182 treated mice. Conclusions: These results indicate that in vivo administration of anti-miRs allows for efficient miRNA targeting and concomitant upregulation of target levels. These results suggest that anti-miR-182 is a promising therapeutic strategy for metastatic melanoma. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Regulus Therapeutics Isis Pharmaceuticals