Histone deacetylase inhibitor panobinostat induces clinical responses with associated alterations in gene expression profiles in cutaneous T-cell lymphoma

Ellis, L; Pan, Y; Smyth, GK; George, DJ; McCormack, C; Williams-Truax, R; Mita, M; Beck, J; Burris, H; Ryan, G; Atadja, P; Butterfoss, D; Dugan, M; Culver, K; Johnstone, RW; Prince, HM

Author(s): Ellis, L; Pan, Y; Smyth, GK; George, DJ; McCormack, C; Williams-Truax, R; Mita, M; Beck, J; Burris, H; Ryan, G; Atadja, P; Butterfoss, D; Dugan, M; Culver, K; Johnstone, RW; Prince, HM;
Details: Publication Year 2008-07-15,Volume 14,Issue #14,Page 4500-4510
Journal Title: CLINICAL CANCER RESEARCH
Publication Type: Journal Article
Abstract: Purpose: 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. Experimental Design: 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.
Publisher: AMER ASSOC CANCER RESEARCH
Keywords: SUBEROYLANILIDE HYDROXAMIC ACID; RECEPTOR COUP-TFII; CYCLIN D1; MULTIPLE-MYELOMA; III TRIAL; CANCER; LBH589; THERAPY; SAHA; CLASSIFICATION
Publisher's Version: https://doi.org/10.1158/1078-0432.CCR-07-4262
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2008-07-15 12:00:00