C-MYC antisense phosphosphorodiamidate morpholino oligomer inhibits lung metastasis in a murine tumor model

Abstract

c-MYC amplification and overexpression has been correlated with progression and chemotherapy resistance in lung cancer. AVI-4126, a neutral antisense phosphorodiamidate morpholino oligomer (PMO) has been identified to specifically inhibit c-MYC expression in multiple disease models and identified in Phase I clinical studies to be safe and bioavailable in solid tumors. The present study evaluates AVI-4126 on the development of lung metastasis in the LLC1 syngeneic murine tumor model. Further, this is the first study to show in vivo mis-splicing of c-MYC post-AVI-4126 treatment. Subcutaneous administration of AVI-4126 at local tumor site (50 microg/day) for 3 cycles of 5 days a week starting day 1 post-tumor cell implantation showed significantly decreased tumor burden, number of tumorlets formed in the lung in comparison to saline or control PMO treatment groups, although no significant reduction of the subcutaneous tumor was observed. AVI-4126 treated lung had markedly reduced mitotic activity but higher rate of apoptosis compared to the controls. HPLC-based analysis of tumor and lung lysates confirmed the presence of intact PMO. In addition to decrease in c-MYC expression, a moderate reduction in the levels of MMP-9 mRNA, a pro-angiogenic extracellular matrix protein postulated to be involved in extravasation of cells from the localized tumor or implantation into the distant metastatic site was observed in the LLC1 tumor tissue of AVI-4126 treated animals. The study results are significant in the development of novel anti-tumoral therapeutic strategies directed to c-MYC-overexpressing tumors and establish AVI-4126 as a strong clinical candidate for metastatic disease.