Olsen EA, Kim YH, Kuzel TM, Pacheco TR, Foss FM, Parker S, Frankel SR, Chen C, Ricker JL, Arduino JM, Duvic MPhase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneousT-cell lymphoma. J Clin Oncol 25: 3109-3115
ABSTRACT To evaluate the activity and safety of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid) in persistent, progressive, or recurrent mycosis fungoides or Sézary syndrome (MF/SS) cutaneous t-cell lymphoma (CTCL) subtypes.
Patients with stage IB-IVA MF/SS were treated with 400 mg of oral vorinostat daily until disease progression or intolerable toxicity in this open-label phase IIb trial (NCT00091559). Patients must have received at least two prior systemic therapies at least one of which included bexarotene unless intolerable. The primary end point was the objective response rate (ORR) measured by the modified severity weighted assessment tool and secondary end points were time to response (TTR), time to progression (TTP), duration of response (DOR), and pruritus relief ( > or = 3-point improvement on a 10-point visual analog scale). Safety and tolerability were also evaluated.
Seventy-four patients were enrolled, including 61 with at least stage IIB disease. The ORR was 29.7% overall; 29.5% in stage IIB or higher patients. Median TTR in stage IIB or higher patients was 56 days. Median DOR was not reached but estimated to be >or = 185 days (34+ to 441+). Median TTP was 4.9 months overall, and 9.8 months for stage IIB or higher responders. Overall, 32% of patients had pruritus relief. The most common drug-related adverse experiences (AE) were diarrhea (49%), fatigue (46%), nausea (43%), and anorexia (26%); most were grade 2 or lower but those grade 3 or higher included fatigue (5%), pulmonary embolism (5%), thrombocytopenia (5%), and nausea (4%). Eleven patients required dose modification and nine discontinued due to AE.
Oral vorinostat was effective in treatment refractory MF/SS with an acceptable safety profile.
- SourceAvailable from: Michael P Pollastri
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- "Hepatitis C viral infection of cultured hepatoma cells causes hypoacetylation of histones and decreased Hepcidin expression, while treatment with the pan-HDAC inhibitor, trichostatin A, increases Stat3 binding to the Hepcidin promoter  and enhances Hepcidin expression  . Vorinostat has been approved for the treatment of refractory cutaneous T-cell lymphoma  and thus may be amenable to clinical investigation in patients with iron overload syndromes who produce inappropriately low levels of Hepcidin. "
ABSTRACT: Hepcidin, a peptide hormone produced in the liver, decreases intestinal iron absorption and macrophage iron release via effects on ferroportin. Bone morphogenic protein and Stat3 signaling regulate Hepcidin's transcription. Hepcidin is a potential drug target for patients with iron overload syndromes because its levels are inappropriately low in these individuals. To generate a tool for identifying small molecules that modulate Hepcidin expression, we stably transfected human hepatocytes (HepG2) cells with a reporter construct containing 2.7 kb of the human Hepcidin promoter upstream of a firefly reporter gene. We used high throughput methods to screen 10,169 chemicals in duplicate for their effect on Hepcidin expression and cell viability. Regulators were identified as chemicals that caused a change > 3 standard deviations above or > 1 standard deviation below the mean of the other chemicals (z-score > 3 or < 1), while not adversely affecting cell viability, quantified by fluorescence assay. Following validation assays, we identified 16 chemicals in a broad range of functional classes that promote Hepcidin expression. All of the chemicals identified increased expression of bone morphogenic protein-dependent and/or Stat3-dependent genes, however none of them strongly increased phosphorylation of Smad1,5,8 or Stat3.Blood Cells Molecules and Diseases 12/2014; 53(4). DOI:10.1016/j.bcmd.2014.06.002 · 2.33 Impact Factor
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- "The HDAC inhibitor panobinostat combined with azacitidine could increase the production of interferon (IFN)-γ and interleukin (IL)-2 in patients with acute myeloid leukemia, which plays a crucial role in anti-leukemic immunity . In addition, another HDAC inhibitor vorinostat was effective in the treatment of refractory lymphoma in a phase II clinical trial . Most importantly , the HDAC inhibitor LAQ824 was able to increase IMinduced cell growth inhibition and apoptosis in CML cells . "
ABSTRACT: Imatinib (IM) represents a breakthrough in the treatment of chronic myeloid leukemia (CML) by inhibiting the activity of Bcr-Abl tyrosine kinase. However, many patients exhibit resistance to IM in the clinic. Recent studies have indicated that sirtuin 1 (SIRT1), a class III histone deacetylase (HDAC), plays an important role in leukemogenesis. In addition, some HDAC inhibitors are being tested to determine their anti-cancer activities in clinical trials. Divalproex sodium (DVPX), a first-line treatment for epilepsy, is also a HDAC inhibitor. However, it is unclear whether the anti-leukemic effects of IM in combination with DVPX on CML cells are related to SIRT1. The aim of this study was to investigate the effects of IM in combination with DVPX on cell viability, apoptosis, and cell cycle arrest in CML cells and to explore the underlying mechanisms. It was found that DVPX enhanced IM-induced cell growth inhibition, apoptosis and cell cycle arrest in K562-S and K562-G cells. Surprisingly, the level of p-Bcr-Abl was similar in K562-S and K562-G cells. Moreover, IM combined with DVPX had no effects on the phosphorylation of Bcr-Abl and its downstream target STAT5. Further study revealed that SIRT1 expression was higher in K562-G cells compared with K562-S cells. DVPX enhanced the inhibitory effect of IM on SIRT1 expression in K562-S and K562-G cells. Furthermore, knockdown of SIRT1 promoted apoptosis of K562-G cells treated with IM and DVPX. These results indicate that DVPX may increase the sensitivity of CML cells to IM and reverse IM resistance by regulating SIRT1 expression. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.Cancer Letters 10/2014; 356(2). DOI:10.1016/j.canlet.2014.10.033 · 5.62 Impact Factor
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- "Defining (and restoring) the “normal” epigenetic landscape has consequently been the focus of active investigation, and has already generated breakthroughs in cancer detection, treatment, and prognosis. Swift approval of epigenetically targeted drugs by the US Food and Drug Administration (FDA) for hematologic conditions has cemented its role in the clinical sphere1–4 (Table 1), and many phase II and III clinical trials are under way for multiple conditions, including solid malignancies.5–7 Below, we highlight the interface between the genome and epigenome and examine the clinical impact facilitated by current and future epigenetic agents. "
ABSTRACT: The emergence of epigenetic mechanisms as key regulators of gene expression has led to dramatic advances in understanding cancer biology. Driven by complex layers that include aberrant DNA methylation and histone modification, epigenetic aberrations have emerged as critical processes that disrupt cellular machinery and homeostasis. Recent discoveries have already translated into successful clinical trials and improved patient care, with several agents approved for hematologic disease and others undergoing study. As the field matures, substantial challenges persist that will require resolution. These include the need to decipher more fully the interplay between the epigenetic and genetic machinery, patient selection and improving treatment efficacy in solid tumors, and optimizing combination therapies to counteract chemoresistance and minimize adverse effects. Here, we review recent progress in epigenetic treatments and consider their implications for future cancer therapy.OncoTargets and Therapy 03/2013; 6:223-32. DOI:10.2147/OTT.S34680 · 2.31 Impact Factor