Mini-reviewDevelopment of the pan-DAC inhibitor panobinostat (LBH589): Successes and challenges
Introduction
In recent years, considerable evidence has emerged to suggest that, in addition to genetic mutations, epigenetic changes also play a critical role in the onset of cancer and its progression [1]. Epigenetic changes are defined as heritable changes in gene expression that are not due to any alteration in the DNA sequence, and most commonly include increased methylation of CpG islands within DNA gene promoter regions and post-translational modifications on histone proteins [1], [2], [3]. Changes to the patterns of epigenetic modification are common in cancer and evidence suggests that epigenetic dysregulation may be a preliminary transforming event frequently observed in benign neoplasias and early stage tumors [4], [5].
DNA and histones provide the main building blocks for nucleosomes, the structural units of chromatin that are important for packaging eukaryotic DNA. Changes in the structural configuration of chromatin to a relatively active (open) or inactive (condensed) form alters the accessibility of DNA for transcription, ultimately affecting gene expression [6]. One of the major ways by which transcription factor binding to DNA is regulated is through changes in chromatin conformation, which in turn is governed by chemical modifications such as the acetylation and deacetylation of lysine residues in the amino terminal tails of the core nucleosomal histones. The changes to core histone acetylation is under the control of opposing activities of the enzymes histone deacetylase (HDAC) and histone acetylase (HAT), leading to changes in gene expression, which includes genes involved in cell cycle regulation, differentiation and apoptosis. Acetylation is generally linked to an ‘open’ chromatin state that is ready for transcription or that corresponds to actively transcribed genomic regions, whereas deacetylation is associated with a closed or inactive state, leading to gene repression. The relative degree of histone acetylation and deacetylation therefore controls the level at which a gene is transcribed.
Although histone proteins were traditionally considered to be the primary focus for HDAC and HAT activities, there is now increasing evidence to suggest that acetylation also plays a crucial role in contexts other than histone and DNA-dependent processes. A considerable number of non-histone proteins that play an important role in cell cycle proliferation and apoptosis have been identified as regulated by HAT and HDAC. These include transcription factors such as p53, NF-κB and E2F1, which play key roles in tumorigenesis and anti-tumor response, as well as proteins that do not directly regulate gene expression but instead regulate DNA repair (Ku70), the cellular cytoskeleton (α-tubulin) and protein stabilisation (Hsp90) [7]. Notably, among non-histone HDAC substrates, Hsp90 plays a major role in the proper folding and stability of several major oncoproteins. HDAC activity also regulates cell protein turnover via the aggresome pathway, which if disrupted, results in the accumulation of polyubiquitinated misfolded protein aggregates, leading to cell stress and caspase-dependent apoptosis [8]. These observations have extended the mechanism of anti-tumor activity of deacetylase inhibitors to include effects on non-histone proteins, implicated in multiple oncogenic pathways, in conjunction with epigenetic changes.
Section snippets
HDAC as a potential target for the discovery of anticancer drugs
HDACs can be divided into two groups: the zinc-dependent HDACs comprising Class I (HDACs 1, 2, 3 and 8 localized to the nucleus), Class II a/b (HDACs 4, 5, 6, 7, 9 and 10 found in the nucleus and cytoplasm) and Class IV (HDAC11); and the zinc-independent, NAD-dependent Class III sirtuin enzymes [9]. Important targets for Class I HDACs are histones and other proteins, such as the transcription factor p53. Class II HDACs act predominantly on non-histone proteins, including Hsp90, which is the
Panobinostat – a novel HDAC inhibitor
The HDAC inhibitors are a group of structurally diverse, targeted anticancer agents of which several are currently in clinical development. HDAC inhibitors are characterized as Class I-specific or as pan-deacetylase (pan-DAC) inhibitors, denoting activity against both Classes I and II HDACs [15]. Class I-specific inhibitors include MGCD0103, MS-275 and romidepsin (depsipeptide). Pan-DAC inhibitors include panobinostat (LBH589), vorinostat (suberoylanilide hydroxamic acid, SAHA) and belinostat
Conclusion
The development of HDAC inhibitors has been and still is associated with a number of challenges. As a multi-class, multi-member target family, the specific HDAC class or isoforms responsible for tumorigenesis have yet to be elucidated and, in terms of the pan-DAC inhibitors, it is unclear which isoform(s) are responsible for mediating anti-tumor activity. Furthermore, modulation of epigenetic and multiple non-epigenetic mechanisms hamper the identification of specific mechanistic actions
Conflicts of Interest
Peter Atadja is an employee of Novartis Institutes for Biomedical Research, a division of Novartis AG and the developer of panobinostat.
Acknowledgements
I would like to thank all the panobinostat team members (past and present) at Novartis AG, the study investigators and study patients for the important contributions that they have made during the development of panobinostat.
In addition, I would like to acknowledge Dina Marenstein of Chameleon Communications International, who provided editorial support with funding from Novartis Oncology.
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