Vorinostat is a histone deacetylase inhibitor approved for treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies and is under evaluation for the treatment of several other hematologic and solid malignancies. We studied gene expression changes in peripheral blood mononuclear cells (PBMCs) collected in a Phase I pharmacokinetic/pharmacodynamic trial in patients with advanced refractory cancer. Patients were treated with single and multiple doses of 400 mg of vorinostat. PBMCs were collected pre-dose and 2, 4, 8, 14, and 24 hr after a single-dose administration of vorinostat. Samples were evaluated for gene expression and histone acetylation. Acetylated histone H3 accumulated in PBMCs 4 to 14 hours after ingestion of a single 400-mg oral dose of vorinostat. Maximum accumulation occurred between 4 and 8 hours post-dose displaying a greater than 2-fold mean change from baseline. Significant differential gene expression relative to pre-dose was observed at each time point post-dose with a peak number of differentially expressed genes at 8 hrs post-dose. Discriminant analysis showed ~75% accuracy for distinguishing between treated and untreated samples at 2, 4, and 14 hr post-dose and, 100 % accuracy at 8 hr, and 50% accuracy at 24 hr, all based on leave-one-out cross validation. Classification of treated versus untreated PBMC samples using biomarkers derived from vorinostat response data in a panel of human lymphoma cell lines (pre-dose vs. 2-8 hr post-dose) was 100 % accurate for samples collected at 2-8 hr post-dose. The same classifier applied to treated samples at 14 hr and 24 hr produced scores more negative than in untreated samples. The major pattern of changes in gene expression exhibited the following time course: A rise in amplitude from 2 to 8 hr, peaking at 4 to 8 hr, and then reversing at 14 to 24 hr with a trend back towards baseline at 24 hr. A large set of genes follow this pattern with prominent downregulation of MYC and upregulation of GADD45B, PUMA, and ABCB1. At 2 to 8 hr post-dose this pattern correlated with increased histone acetylation, which also peaked at 8 hr post-dose. In addition to the major pattern of gene expression changes, which were similar across clinical and preclinical samples, significant regulation of cytokine protein expression was observed in the clinical data set. Upregulation of the Th1 cytokine, interferon gamma, and downregulation of the Th2, cytokine IL4, appeared early post-dose, peaked at 4 to 8 hr and was maintained 14 to 24 hr post-dose. Further evaluation of changes in gene expression profiles following treatment with vorinostat in advanced solid and hematologic malignancies and validation of these findings are warranted.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA