Advances in the development of histone deacetylase inhibitors

RThe drive to develop improved treatments of cancer has resulted in the development of a number of strategies designed to regulate transcription. The retinoic acids represent one early target (see our recent report “The retinoids: Therapeutic & pharmaceutical opportunities”). As described in this report, our understanding of the molecular biology behind the retinoic acids is rapidly expanding and opportunities for improved treatments of cancer are thus expected. The field of histone deacetylation represents a second area receiving much interest in respect to transcriptional control. This field centers on the now generally accepted view that chromatin structure is plastic and that histone (de)acetylation regulates genome structure and hence transcription. Modifying this process by histone deacetylase (HDAC) inhibitors can therefore regulate, potentially in a highly specific manner, transcription thereby offering a much more targeted approach to cytostasis than currently available. Information relating to histone deacetylation is emerging with breathtaking rapidity with over 1 new article currently being published every day. In response to this activity we recently published one of the most comprehensive overview of the pharmaceutical potential of HDAC inhibitors to date (Click here to access "Histone deacetylase inhibitors: Redefining pharmaceutical approaches to the treatment of cancer").

At the time of publication of our histone deacetylase inhibitor report suberoylanilide hydroxamic acid (SAHA) was one of the most advanced candidate inhibitors having been entered into a phase I trial by Aton pharma. Results from this trial have recently been published. SAHA when administered iv is well tolerated and was shown to produce an accumulation of acetylated histones in peripheral blood mononuclear cells up to 4 h postinfusion suggesting that treatment was sufficient to inhibit histone deacetylation. This biological response was mirrored by an objective tumor regression and clinical improvement in tumor related symptoms in 4 out of 29 patients (2 with lymphoma and 2 with bladder cancer). According to Aton Pharma separate Phase I studies have shown oral doses of SAHA to be readily bioavailable, and result in prolonged (8-10 hours) inhibition of HDAC in the blood cells of patients and hence the key milestones of the SAHA Phase I program have been met. Consequently the oral formulation of SAHA has now entered into phase II to determine the activity of oral SAHA in several solid tumors and in hematological tumors. Two single-agent Phase II trials, one in patients with cutaneous T cell lymphoma or peripheral T cell lymphoma and another in patients with recurrent or metastatic squamous cell cancer of the head and neck were initiated in October, 2002.