Epigenetic modification by small-molecule histone deacetylase inhibitors (HDAC-Is) has been a promising new antineoplastic approach for various solid and hematological malignancies, particularly for cutaneous T-cell lymphoma (CTCL). Vorinostat, a pan-HDAC-I and, most recently, romidepsin, a bicyclic pan-HDAC-I, have been US FDA approved for treatment of relapsed or refractory CTCL. However, because many patients do not reach the 50% partial response mark and response is not always sustainable, overcoming HDAC-I resistance by adding other agents or finding more selective molecules is an important clinical problem in realizing the full clinical potential of HDAC-Is. In this review, we discuss the molecular basis for HDAC-I function in cancer, the clinical response and side-effect profile experienced by CTCL patients, and the progress made in attempting to identify biomarkers of response and resistance, as well as synergistic combination therapies.

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Epigenetic modification with small molecule histone deacetylase inhibitors has been a promising new anti-neoplastic approach for various solid and hematological malignancies, particularly cutaneous T-cell lymphoma (CTCL). Oral vorinostat was the first histone deacetylase inhibitor approved to enter the clinical oncology market for treating CTCL patients who have progressive, persistent, or recurrent disease after failing two systemic therapies. In two phase II clinical trials, oral vorinostat was found to be safe and effective at a dose of 400 mg/day, with an overall response rate of 24%-30% in heavily pretreated patients with advanced CTCL, including those with large-cell transformed mycosis fungoides and Sézary syndrome. About half of CTCL patients receiving vorinostat also experienced substantial relief in pruritus and thus a marked improvement in quality of life. A subsequent follow-up study reported long-term safety and clinical benefits of vorinostat in patients with refractory CTCL, regardless of previous treatment failures. The most frequent side effects of vorinostat include gastrointestinal symptoms, fatigue, and thrombocytopenia. These adverse reactions are dose-related and reversible upon cessation of therapy. Preclinical studies have supported the therapeutic potential of vorinostat by demonstrating in vitro and in vivo anti-tumor activities against CTCL, including selective induction of apoptosis in malignant T cells, inhibition of angiogenesis, suppression of signal transducer and activator of transcription proteins, and up-regulation of pro-apoptotic proteins. Identification of biomarkers of response and resistance will help select CTCL patients most likely to benefit from treatment and guide the design of effective combination therapies.