Antisense therapy for cancer

Abstract

Antisense oligonucleotides (ASOs) offer one approach to target genes involved in cancer progression, particularly those that are not amenable to small-molecule or antibody inhibition. ASOs inhibit translation through a mechanism that involves the formation of an mRNA–ASO duplex, leading to RNase-H-mediated cleavage of the target mRNA. Several useful modifications of ASO backbones have yielded compounds that show good tissue distribution and increased resistance to nuclease digestion. ASO drugs are evolving through improved chemical modifications to prolong in vivo half-life, increase potency and reduce toxicity. The most promising targets for antisense therapy are those that become upregulated during tumorigenesis and several of these, including BCL2, protein kinase Cα, clusterin, X-linked inhibitors of apoptosis and survivin, are currently in or have finished early-phase clinical trials. A disappointing lack of clinical efficacy for some ASOs indicates that challenges remain. However, the advanced chemistry incorporated into the second-generation ASOs has significant promise for the future. A recently completed prostate cancer pre-surgery trial provides proof of concept that the second-generation 2'-MOE OGX-011 can potently suppress the target protein clusterin in humans.