SPC2968—A novel Hif-1α antagonist for treatment of clear cell renal cell carcinoma

14581 Background: SPC2968 is a short (16-mer), oligonucleotide antagonist of Hif-1α mRNA in which potency has been enhanced through incorporation of Locked Nucleic Acid. Over-expression of Hif-1α has been correlated with increased vascularisation, metastatic potential and poor clinical outcome in a variety of malignancies, including Renal Cell Carcinoma (RCC) of clear cell aetiology, where Hif-1α dysregulation, brought about by mutations in the von Hippel Lindau gene, appears to play a major pathogenic role. Methods: In vitro, human cancer and endothelial cells grown under hypoxic conditions were used to evaluate the effect of SPC2968 on mRNA and protein to Hif-1α as well as phenotypic effects, measured by quantitative polymerase chain reaction (QPCR), Western blotting and biochemical/cellular assays. QPCR was also used to measure mRNA levels in SPC2968-treated mice, while the effects of the drug on tumour growth and vascularisation were evaluated in xenografts. To assess biodistribution in vivo, tritium-labelled SPC2968 was injected intravenously. Results: In vitro, SPC2968 at 1nM reduced both mRNA and protein levels of Hif-1α in cancer cell lines and downregulated two downstream targets of Hif-1, VEGF and MMP-2.Treatment also induced apoptosis in tumour cells and prevented tube formation by endothelial cells in vitro. Parenteral administration of SPC2968 in mice yielded potent inhibition of Hif-1α and VEGF mRNA in several tissues, including kidney, liver, and colon. Radioactively labelled SPC2968 distributed to kidney, liver, colon, bone marrow, lymph nodes and skin. Preclinical studies investigating acute and sub-acute toxicity and safety pharmacology of SPC2968 are completed, and SPC2968 was well tolerated. Conclusions: SPC2968 is an effective suppressor of Hif-1α mRNA and Hif-1α-regulated genes in vitro and in vivo and has shown good tissue biostability and biodistribution in rodents. Preclinical safety studies have been completed, and SPC2968 is ready for clinical testing. A phase I/II, dose-escalating study of SPC2968 in clear cell RCC in the US and the EU is planned to be submitted by mid 2006. [Table: see text]