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Clinical studies of antisense therapy in cancer
1Oncology Division, 703 Welch Road, Suite H4, Palo Alto, CA 94304, USA. ayuen@stanford.edu
Abstract:
The ability to target and inhibit individual gene expression with antisense oligonucleotides has shown promising activity in preclinical cancer models. Recent clinical studies have tested antisense compounds directed against seven cancer related genes including p53, bcl-2, c-raf, H-ras, protein kinase C-alpha, and protein kinase A. Class specific effects of the phosphorothioate backbone common to the first generation of antisense compounds have dominated the side effects of these oligonucleotides. Inhibition of target gene expression has been modest at most, and clinical activity has been primarily anecdotal. Combinations of the antisense compounds with chemotherapy and second-generation oligonucleotides offer promise that these agents might become a standard part of future cancer therapy.
Insights
Antisense oligonucleotides show potential in preclinical cancer models but face challenges in clinical trials. Combining these agents with chemotherapy may improve future cancer treatment efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Antisense oligonucleotides (ASOs) are emerging as a therapeutic strategy for cancer.
- Preclinical studies demonstrate ASOs' ability to inhibit gene expression and show anti-cancer activity.
- Clinical investigations have explored ASOs targeting key cancer-related genes such as p53 and bcl-2.
Purpose of the Study:
- To evaluate the clinical efficacy and challenges of antisense oligonucleotides in cancer therapy.
- To identify the factors limiting the success of first-generation antisense compounds.
- To explore potential strategies for enhancing the therapeutic impact of ASOs.
Main Methods:
- Review of recent clinical studies involving antisense compounds targeting seven cancer-related genes.
- Analysis of side effects associated with the phosphorothioate backbone of first-generation ASOs.
- Assessment of target gene inhibition and clinical activity reported in trials.
Main Results:
- First-generation ASOs, particularly those with phosphorothioate backbones, exhibit class-specific side effects.
- Modest inhibition of target gene expression and primarily anecdotal clinical activity were observed.
- Significant challenges remain in achieving robust therapeutic effects with current ASO technology.
Conclusions:
- Antisense oligonucleotides have shown promise but face limitations in clinical cancer treatment.
- Side effects and modest target inhibition hinder the widespread application of first-generation ASOs.
- Combination therapies with chemotherapy and next-generation ASOs represent a promising avenue for future cancer treatment.