title: Histone deacetylase inhibitor panobinostat induces clinical responses with associated alterations in gene expression profiles in cutaneous T-cell lymphoma.
abstract: OBJECTIVE
  Histone deacetylase inhibitors can alter gene expression and mediate diverse antitumor activities. Herein, we report the safety and activity of the histone deacetylase inhibitor panobinostat (LBH589) in cutaneous T-cell lymphoma (CTCL) and identify genes commonly regulated by panobinostat.
  
  
  METHODS
  Panobinostat was administered orally to patients with CTCL on Monday, Wednesday, and Friday of each week on a 28-day cycle. A dose of 30 mg was considered excessively toxic, and subsequent patients were treated at the expanded maximum tolerated dose of 20 mg. Biopsies from six patients taken 0, 4, 8, and 24 h after administration were subjected to microarray gene expression profiling and real-time quantitative PCR of selected genes.
  
  
  RESULTS
  Patients attained a complete response (n = 2), attained a partial response (n = 4), achieved stable disease with ongoing improvement (n = 1), and progressed on treatment (n = 2). Microarray data showed distinct gene expression response profiles over time following panobinostat treatment, with the majority of genes being repressed. Twenty-three genes were commonly regulated by panobinostat in all patients tested.
  
  
  CONCLUSIONS
  Panobinostat is well tolerated and induces clinical responses in CTCL patients. Microarray analyses of tumor samples indicate that panobinostat induces rapid changes in gene expression, and surprisingly more genes are repressed than are activated. A unique set of genes that can mediate biological responses such as apoptosis, immune regulation, and angiogenesis were commonly regulated in response to panobinostat. These genes are potential molecular biomarkers for panobinostat activity and are strong candidates for the future assessment of their functional role(s) in mediating the antitumor responses of panobinostat.
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Leigh
authors.initials: L
authors.lastname: Ellis
authors.forename: Yan
authors.initials: Y
authors.lastname: Pan
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: George
authors.forename: Chris
authors.initials: C
authors.lastname: McCormack
authors.forename: Roxanne
authors.initials: R
authors.lastname: Williams-Truax
authors.forename: Monica
authors.initials: M
authors.lastname: Mita
authors.forename: Joachim
authors.initials: J
authors.lastname: Beck
authors.forename: Howard
authors.initials: H
authors.lastname: Burris
authors.forename: Gail
authors.initials: G
authors.lastname: Ryan
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
authors.forename: Dale
authors.initials: D
authors.lastname: Butterfoss
authors.forename: Margaret
authors.initials: M
authors.lastname: Dugan
authors.forename: Kenneth
authors.initials: K
authors.lastname: Culver
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
authors.forename: H Miles
authors.initials: HM
authors.lastname: Prince
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000187:drug effects; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007211:Indoles; D016410:Lymphoma, T-Cell, Cutaneous / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D000077767:Panobinostat; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat; D006655:Histone Deacetylases