Abstract
Abstract 4396: Evaluation of gene expression and transcriptional activation in patients treated with vorinostat
Cancer research (Chicago, Ill.), Vol.71(8_Supplement), pp.4396-4396
04/15/2011
DOI: 10.1158/1538-7445.AM2011-4396
Abstract
Abstract
Background: Vorinostat is a histone deacetylase (HDAC) inhibitor that is approved for treatment of cutaneous T-cell lymphoma and is being investigated in a number of solid tumors. Inhibition of HDAC by vorinostat leads to an accumulation of acetylated histones which induces apoptosis though a mechanism that is not completely characterized. This study was performed to assess the potential mechanisms responsible for induction of apoptosis following treatment with vorinostat. Methods: Sixty subjects with advanced malignancies received vorinostat orally days 1-14 combined with bortezomib IV on days 2, 4, 8, and 11 of a 21-day cycle. Peripheral blood mononuclear cells (PBMCs) were collected before and 2hr and 6hr after dosing on Days (D) 1 and 9. Paired tumor biopsies were obtained in ten patients on D0 and D9. Gene expression of downstream targets was evaluated by semi-quantitative RT-PCR in PBMCs, and the interaction between candidates genes and acetylated histone H3 were evaluated in biopsies by the chromatin precipitation assay. A nonparametric Wilcoxon signed rank test was used to examine changes from the pre-treatment value of 1 on D1 based on complete case analysis without multiplicity adjustment. Results: p21, Nur77 and HSP70 gene expression in PBMCs were all significantly induced two hours after vorinostat administration compared to baseline (Table 1). AKT, ERB1 and ERB2 expression were not statistically significantly altered in PBMCs. The expression of all targets increased in tumor biopsies by Day 9, with p21 2.37, Nur77, 1.33 and HSP70 2.35 times baseline expression levels. The chromatin precipitation assay demonstrated that Nur77, HSP70 and p21 interacted with acetylated histone H3, after nine days of treatment with vorinostat, in tissue biopsies. Conclusion: This data suggests that acetylated histones interact transcriptionally with p21, Nur77 and HSP77 to induce gene expression and are a potential mechanism by which vorinostat induces apoptosis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4396. doi:10.1158/1538-7445.AM2011-4396
Details
- Title: Subtitle
- Abstract 4396: Evaluation of gene expression and transcriptional activation in patients treated with vorinostat
- Creators
- Jill M. KolesarElim LauSongwon SeoJens EickhoffKyungMan KimAnne TraynorHoward BaileyGeorge WildingWilliam Schelman
- Resource Type
- Abstract
- Publication Details
- Cancer research (Chicago, Ill.), Vol.71(8_Supplement), pp.4396-4396
- Publisher
- AMER ASSOC CANCER RESEARCH; PHILADELPHIA
- DOI
- 10.1158/1538-7445.AM2011-4396
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Language
- English
- Date published
- 04/15/2011
- Academic Unit
- Pharmacy; Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984696555002771
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