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Current Treatment Options for Cutaneous T-cell Lymphoma
Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of extranodal non-Hodgkin’s lymphomas characterized by their surface markers and biological behavior. Mycosis fungoides (MF) and its leukemic variant Sézary syndrome (SS) are the most frequently encountered CTCLs resulting from a progressive clonal expansion of CD4+CD45RO+CLA+CCR+ helper/memory T cells. The malignant clones may have loss of common T-cell markers (CD7 and/or CD26).1 Progression of MF/SS is accompanied by clonal dominance,2 secretion of Th2 cytokines,3 impaired immune responses, and cell growth advantage.1,4 The malignant T cells exhibit abnormal apoptotic mechanisms, such as loss of Fas or expression of Bcl-2, that result in loss of activation-induced cell death, prolonged life span, and accumulation. These cells typically become resistant to treatment over time.5
The choice of therapy should be based on the stage of disease. Patients with early MF have disease limited to the skin (T1–2N0–1M0; IA–IIA) and can be put into remission with topical agents (topical steroids, retinoids, phototherapy or mustargen). More advanced or late stages (T1–4N0 –3M0–1; IIB–IVB) of MF or SS require both systemic and skin-directed therapies. Patients who have extensive refractory skin involvement, blood involvement, tumors, or nodal disease require systemic therapy. Refractory or extensive skin involvement including SS responds to systemic biologic response modifiers (retinoids, bexarotene, interferon, and denileukin diftitox), skin radiation and photopheresis. Single- or multi-agent chemotherapies are used for patients with large numbers of transformed tumors or nodal/visceral disease. In general, a combination of either sequential or concomitant therapies gives a higher rate of response, but advanced patients often relapse and curative therapy is elusive for most. 1
The US Food and Drug Administration (FDA) approved the histone deacetylase inhibitor (HDAC-I) vorinostat (suberoylanilide hydroxamic acid [SAHA]) in 2006 for the treatment of cutaneous manifestations of CTCL based on data from two phase II clinical trials.6,7 Translational studies have shown that vorinostat has in vitro and in vivo antitumor activity against CTCL.6,8 As such, HDAC-Is represent an attractive new strategy for targeted therapy of advanced CTCL. This article provides a brief overview of the biology of HDACs and HDAC-Is, as well as pre-clinical and clinical studies of vorinostat in CTCL.
Biology of Histone Deacetylases and Their Inhibitors
HDACs and histone acetylases (HATs) are key enzymes that remove or add acetyl groups to proteins including histones.9,10 Histones are acetylated by HATs on their lysine tails, which can then interact with the DNA sugar backbone. When HDACs remove acetyl groups on histones, the DNA becomes compacted, limiting access to transcription factor complexes. HDAC-Is interact with HDACs and block their function.11 HDACs and HATs represent new targets for cancer therapeutics arising from the observation that the balance of aceylation and deacetylation controls transcription of tumor suppressors and other key proteins for cell growth.
To date, four classes of HDAC have been identified (see Table 1).9,10 Class I human HDACs (HDACs 1, 2, 3, and 8) are small, with an approximate molecular mass of 22–55kDa, and are homologous to the yeast HDAC Rpd3. Class II HDACs (HDACs 4, 5, 6, 7, 9, and 10) are larger enzymes with molecular masses between 120 and 135kDa and are related to yeast HDA1 deacetylases. HDAC-Is, including vorinostat, that block class I and II HDACs are known as pan-HDA inhibitors. Class III human HDACs are homologues of yeast Sir2 and require nicotinamide–adenine dinucleotide NAD+ for activity. They also differ from class I and II HDACs in their catalytic site. HDAC11 is more closely related to the class I and II HDACs; however, because it shares a similar level of homology with both classes, it has been assigned as the single class IV HDAC, found in all species evaluated except fungi. The key catalytic residues have been conserved in class I, II, and IV HDACs. Class I HDACs are primarily nuclear in localization and are ubiquitous. Class II HDAC expression is tissue-restricted; some shuttle between the nucleus and the cytoplasm, whereas others are primarily cytoplasmic. In cancer cells, class I and II HDACs have been shown to be over-expressed, aberrantly recruited to oncogenic transcription factors, and mutated. As such, they represent potential key targets for small-molecule inhibitors.9–11
There are currently five classes of HDAC-I grouped according to their chemical structure and affinity for different HDACs (see Table 2).12 Several pan-HDAC-Is have shown activity in CTCL, especially vorinostat (SAHA), pnobinostat (LBH589,) and belinostat (PXD101), as have the more selective inhibitors romidepsin (FK228 or depsipeptide) and SNDX- 275 (formerly MS-275). Vorinostat (Merck, Whitehouse Station, US) was studied in two phase II trials and received FDA approval in October 2006 for treatment of cutaneous manifestations of CTCL in patients who have progressive, persistent, or recurrent disease on or following two prior systemic treatments.6,7 PXD101 and LBH589 are currently in clinical trials in both solid tumors and hematological malignancies, including CTCL.12FK228 (romidepsin, depsipeptide) is a natural product prodrug that is a selective inhibitor of class I HDACs. It has also exhibited considerable activity in CTCL and in peripheral T-cell non-Hodgkin’s lymphomas (PTCLs). SNDX-275 is a non-hydroxamic-based compound that exhibits selectivity for class I HDAC enzymes, and a combination regimen with azacitidine is in phase II development.12