Histone Deacetylase (HDAC) Inhibitors in Recent Clinical Trials for Cancer Therapy

Abstract

Heritable changes in gene expression that are not based upon alterations in the DNA sequence are defined as epigenetics. The most common mechanisms of epigenetic regulation are the methylation of CpG islands within the DNA and the modification of amino acids in the N-terminal histone tails. In the last years, it became evident that the onset of cancer and its progression may not occur only due to genetic mutations but also because of changes in the patterns of epigenetic modifications. In contrast to genetic mutations, which are almost impossible to reverse, epigenetic changes are potentially reversible. This implies that they are amenable to pharmacological interventions. Therefore, a lot of work in recent years has focussed on the development of small molecule enzyme inhibitors like DNA-methyltransferase inhibitors or inhibitors of histonemodifying enzymes. These may reverse misregulated epigenetic states and be implemented in the treatment of cancer or other diseases, e.g., neurological disorders. Today, several epigenetic drugs are already approved by the FDA and the EMEA for cancer treatment and around ten histone deacetylase (HDAC) inhibitors are in clinical development. This review will give an update on recent clinical trials of the HDAC inhibitors used systemically that were reported in 2009 and 2010 and will present an overview of different biomarkers to monitor the biological effects.

The pan-HDAC inhibitor panobinostat acts as a sensitizer for erlotinib activity in EGFR-mutated and -wildtype non-small cell lung cancer cells

“…Histone deacetylase inhibitors (HDACis) exert their anticancer effects by increasing acetylation of core histones as well as non-histone proteins, thereby influencing gene transcription and ultimately leading to the induction of apoptosis, differentiation or degradation of misfolded proteins [ 7 ]. To date, three HDACis, vorinostat (SAHA), romidepsin and panobinostat (LBH-589, PS), have been FDA-approved for the treatment of cutaneous and peripheral T-cell lymphoma and multiple myeloma.…”

Histone acetyltransferase inhibitors block neuroblastoma cell growth in vivo

“…In clinical trials, epigenetic inhibitors have often shown weak efficacy when used as single agents. 44 Hence, combination therapy might prove to be the key to successful implementation of epigenetic inhibitors in cancer treatment. The anthracycline doxorubicin is a well-characterized DNA-intercalating drug that is used in the therapy of neuroblastoma, combined with cisplatin, etoposide and cyclophosphamide (CEDC regime).…”

“…This points out to a potential use of HAT inhibitors in combination chemotherapy. For HDAC inhibitors, many such combinations are currently studied in clinical trials 44 and a systematic analysis of synergies of HAT inhibitors with other epigenetic agents but also other classic anticancer drugs is warranted. Furthermore, PU139-treated healthy mice showed significant histone hypoacetylation in bone marrow on all four investigated lysine residues in a short-time exposure experiments confirming target engagnement in vivo .…”

Carbamates as Potential Prodrugs and a New Warhead for HDAC Inhibition

“…Histone deacetylases (HDACs) are some of the best-studied histone modifying enzymes within the still expanding field of epigenetics. They are validated targets for anticancer therapy with five approved drugs on the market and a growing number of HDAC inhibitors in promising clinical trials [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ]. Besides the Sirtuins (class III HDACs) that possess a catalytic mechanism depending on NAD (nicotine adenine dinucleotide), the classical HDACs (classes I, II and IV) are zinc-dependent amidohydrolases.…”