Key Points
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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.
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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.
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Several useful modifications of ASO backbones have yielded compounds that show good tissue distribution and increased resistance to nuclease digestion.
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ASO drugs are evolving through improved chemical modifications to prolong in vivo half-life, increase potency and reduce toxicity.
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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.
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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.
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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.
Abstract
Improved understanding of the molecular mechanisms that mediate cancer progression and therapeutic resistance has identified many therapeutic gene targets that regulate apoptosis, proliferation and cell signalling. Antisense oligonucleotides offer one approach to target genes involved in cancer progression, especially those that are not amenable to small-molecule or antibody inhibition. Better chemical modifications of antisense oligonucleotides increase resistance to nuclease digestion, prolong tissue half-lives and improve scheduling. Indeed, recent clinical trials confirm the ability of this class of drugs to significantly suppress target-gene expression. The current status and future directions of several antisense drugs that have potential clinical use in cancer are reviewed.
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Glossary
- PHOSPHOROTHIOATE BACKBONE
-
The non-bridging phosphoryl oxygen of each nucleotide in an oligomer is replaced with sulphur, which increases resistance to nuclease digestion and prolongs tissue half-life.
- OFF TARGET
-
A non-specific effect of a drug or antisense oligonucleotide that is different from its characterized specific effect on its known target molecule.
- APOPTOTIC RHEOSTAT
-
Describes the dynamic interactions between pro-survival and pro-death signals within a cell that regulate programmed cell death.
- THROMBOCYTOPAENIA
-
Low circulating platelet count (<125 × 109/L), which leads to a reduction in the clotting efficiency of the blood.
- INTENT-TO-TREAT ANALYSIS
-
Patients are analysed according to the treatment group they were randomized to, as opposed to the treatment actually received.
- PER-PROTOCOL ANALYSIS
-
A priori planned analysis of results.
- 2′-O-METHOXYETHYL MODIFICATIONS
-
Modifications of the ribose at the 2′-position with an electronegative substitute such as 2′-O-methyl or 2′-O-methoxy-ethyl group (illustrated in Box 2).
- LEUKOPAENIA
-
Low circulating total white blood cell count, often associated with anticancer drugs, which can predispose the host to infections.
- NEUTROPAENIA
-
Low circulating neutrophil cell count (<2 × 109/L), which is often associated with anticancer drugs and can predispose the host to infections.
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Gleave, M., Monia, B. Antisense therapy for cancer. Nat Rev Cancer 5, 468–479 (2005). https://doi.org/10.1038/nrc1631
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DOI: https://doi.org/10.1038/nrc1631
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