Histone deacetylase inhibitor panobinostat induces clinical responses with associated alterations in gene expression profiles in cutaneous T-cell lymphoma.
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.
Ellis
Leigh
L
Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Pan
Yan
Y
Smyth
Gordon K
GK
George
Daniel J
DJ
McCormack
Chris
C
Williams-Truax
Roxanne
R
Mita
Monica
M
Beck
Joachim
J
Burris
Howard
H
Ryan
Gail
G
Atadja
Peter
P
Butterfoss
Dale
D
Dugan
Margaret
M
Culver
Kenneth
K
Johnstone
Ricky W
RW
Prince
H Miles
HM
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
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat; D006655:Histone Deacetylases