Histone deacetylase 2 (HDAC2): Modulation of HDAC2 and its implication for chronic obstructive airway diseases (COPD) and cancer.

Earlier in 2005, LeadDiscovery published an in depth report on the development of the novel anti-cancer class, the HDAC inhibitors (see Histone deacetylase inhibitors-Moving from the bench to a promising companion for classic and targeted cancer therapies). As this class advances with therapeutic candidates now entering phase II trials, companies are seeking to optimize therapeutic margins by targeting specific isoforms of histone deacetylase that are involved in tumor progression. In a recent NEJM study Prof. Peter Barnes and colleagues demonstrates that the inhibition of HDAC2 could introduce airway risks, possibly exacerbating the severity of chronic obstructive pulmonary diseases (COPD). Conversely and of equal importance the study suggests that the selective induction of HDAC2 could represent a new approach to this frequent and serious condition. Theophylline has been used as an approach to the treatment of airway disorders although its mechanism of action is complicated given the non-selectivity of this drug. One action of theophylline is to induce HDAC2 expression and the NEJM study suggests that the development of theophylline analogues that selectively induce HDAC2 may represent a useful approach to the treatment of COPD. The identification of new therapeutics that can treat COPD is urgently require given the high incidence of this group of diseases and the lack of effective treatments (see Pipeline Insight: Asthma, COPD and Allergic Rhinitis Therapeutics)

Earlier in 2005, LeadDiscovery published an in depth report on the development of the novel anti-cancer class, the HDAC inhibitors (see Histone deacetylase inhibitors-Moving from the bench to a promising companion for classic and targeted cancer therapies). This report, in addition to discussing the proof of concept supporting the development of HDAC inhibitors, evaluated emerging clinical candidates. HDAC activity regulates histone plasticity and hence transcription. Inhibition of this activity reduces the expression of a surprisingly small group of proteins many of which are involved in cancer related processes. Two of the most advanced clinical candidates are Merck's SAHA and Gloucester Pharmaceuticals' FK288 (depsipeptide; FK901228). In May 2005, Gloucester Pharmaceuticals reported phase II data demonstrating the efficacy of FK288 as a single-agent therapy in patients with relapsed or refractory peripheral T-cell lymphoma (press release). These data were the first from a phase II study of an HDAC inhibitor and this study thus represented a milestone in the development of this therapeutic class.

In our histone deacetylase inhibitor report, one of the primary conclusions was that improved subtype specificity is required in order to improve the efficacy and reduce the toxicity risk of the HDAC inhibitor class. At least 11 HDAC subtypes exist. Class I enzymes include HDAC1, 2, 3, 8 and 11, while class II enzymes include HDAC4, 5, 6, 7, 9 and 10. Early inhibitors such as SAHA are non-selective. MethylGene are one of the leaders in the development of selective HDAC inhibitors and in particular MGCD0103 inhibits a specific subset of HDAC isoforms which have been identified by MethylGene using functional genomics as playing a major role in cancer. The target enzymes have not been disclosed, however in our report we conclude that developing dual HDAC1/HDAC8 inhibitors may offer a useful approach to the treatment of cancer and that it is not yet clear whether additional inhibition of HDAC2 and/or HDAC3 would improve the therapeutic window. The results of the NEJM study presented here would suggest that the inhibition of HDAC2 could introduce airway risks, possibly exacerbating the severity of chronic obstructive pulmonary diseases (COPD). Conversely and of equal importance the study suggests that the selective induction of HDAC2 could represent a new approach to this frequent and serious condition.

COPD, an umbrella term for chronic obstructive bronchitis and emphysema, is one of the most prevalent diseases to affect man. Over 600 million people suffer from COPD world-wide with some three million dying as a result each year. COPD is commonly caused by smoking which produces chronic respiratory inflammation, proteolytic breakdown of airway tissue and consequent loss of elastic recoil in the lungs. This serious healthcare problem is paralleled by global sales of around US$2.8 billion which will increase in value significantly over the next decade. This will be driven by the aging population, new approvals and increased awareness. In stark contract to the situation for asthma, therapeutic options for the treatment of COPD are limited and this represents an unmet market. In fact Boehringer Ingelheim’s recently launched Spiriva was the first specific drug for COPD. Advair and Symbicort are also used to treat COPD although they were initially approved as asthma therapeutics and only recently approved for the treatment of COPD. Novel pipeline therapies for the treatment of COPD are sparse and long-acting, dual-action bronchodilator combinations will expand the COPD market (see Pipeline Insight: Asthma, COPD and Allergic Rhinitis Therapeutics) until novel approaches are identified.

HDAC activity has previously been shown to repress the expression of proinflammatory cytokines by alveolar macrophages and in their NEJM study Prof Peter Barnes and colleagues demonstrate reduced HDAC activity in patients with COPD. This appears to result in reduced acetylation of the NF-kappaB binding site within the IL-8 promotor region and hence the expression of this inflammatory cytokine. Levels of acetylation and IL-8 expression increased with disease severity, while HDAC activity correlated with decline in lung function. Reduced HDAC activity was quite selective for COPD since individuals with other respiratory tract conditions associated with inflammation failed to display reduced activity. Further investigation demonstrated that although the mRNA levels of multiple HDAC subtypes were reduced in alveolar macrophages from COPD patients, only HDAC2 protein levels were reduced. HDAC2 has been shown, at least in part, to mediate the anti-inflammatory effect of corticosteroids in COPD patients. Loss of HDAC2 activity may therefore result in reduced therapeutic activity of this class as well as an increase in the expression of proinflammatory cytokines such as IL-8 and an increase in disease severity.

This exciting study carries multiple implications. Firstly it suggests that HDAC2 is actively involved in the etiology and possibly treatment resistance of COPD and thus agents that reintroduce HDAC2 expression may be of therapeutic value. Theophylline has been shown to confer such activity and may drive new approaches to COPD. On the other hand non-selective suppression of HDAC activity by anticancer agents may produce detrimental effects especially in patients with COPD. Since COPD is associated with smoking this may be a particular problem in patients being treated for lung cancer and hence dual HDAC1/HDAC8 inhibition may confer advantages over inhibitors that also target HDAC2.