Unknown,Transcriptomics,Genomics,Proteomics

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The Pelvic Radiation and Vorinostat (PRAVO) Study - Histone Deacetylase Inhibitor Activity

ABSTRACT: The study objective was to propose molecular mechanisms of action of the histone deacetylase inhibitor vorinostat. In the PRAVO phase 1 study, patients that were scheduled to receive pelvic palliative radiation to 30 Gy in 3-Gy fractions for gastrointestinal carcinoma, were enrolled onto four sequential dose levels of vorinostat, starting at 100 mg daily with dose escalation in increments of 100 mg. Endpoints included treatment safety and tolerability, tumor response, and biological activity of vorinostat. For the purpose of identifying biomarkers of vorinostat action, peripheral blood mononuclear cells, representing normal tissue exposed to vorinostat, were used. The samples were collected, one at baseline and two on-treatment samples. The time points for sample collection were chosen based on our previous data from experimental colorectal carcinoma models exposed to vorinostat, demonstrating that the maximum tumor histone acetylation 2-3 hours after drug exposure was restored to baseline after 24 hours. In PRAVO study patients, tumor histone hyperacetylation was observed 3 hours after vorinostat administration. From the 17 patients enrolled onto the PRAVO study, a full set of three samples was obtained from 14 individuals: one baseline sample collected prior to commencement of vorinostat treatment (T0), and two on-treatment samples collected 2 and 24 hours after the patient had received the preceding daily dose of vorinostat (T2 and T24). Individual vorinostat dose levels were 100 mg (D100), 200 mg (D200), 300 mg (D300), or 400 mg (D400).

ORGANISM(S): Homo sapiens

SUBMITTER: Ert Kalanxhi

PROVIDER: E-GEOD-46703 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Gene Expression Profiling of a Mouse Xenograft Model of â??Triple-Negativeâ?? Breast Cancer Brain Metastases With and Without Vorinostat Treatment. Purpose: As chemotherapy and molecular therapy improve the systemic survival of breast cancer patients, the incidence of brain metastases increases. Few therapeutic strategies exist for the treatment of brain metastases because the blood-brain barrier severely limits drug access. We report the pharmacokinetic, efficacy, and mechanism of action studies for the histone deactylase inhibitor vorinostat (suberoylanilide hydroxamic acid) in a preclinical model of brain metastasis of triple-negative breast cancer. Experimental Design: The 231-BR brain trophic subline of the MDA-MB-231 human breast cancer cell line was injected into immunocompromised mice for pharmacokinetic and metastasis studies. Pharmacodynamic studies compared histone acetylation, apoptosis, proliferation, and DNA damage in vitro and in vivo. Results: Following systemic administration, uptake of [14C]vorinostat was significant into normal rodent brain and accumulation was up to 3-fold higher in a proportion of metastases formed by 231-BR cells. Vorinostat prevented the development of 231-BR micrometastases by 28% (P = 0.017) and large metastases by 62% (P < 0.0001) compared with vehicle-treated mice when treatment was initiated on day 3 post-injection. The inhibitory activity of vorinostat as a single agent was linked to a novel function in vivo: induction of DNA double-strand breaks associated with the down-regulation of the DNA repair gene Rad52. Conclusions: We report the first preclinical data for the prevention of brain metastasis of triple-negative breast cancer. Vorinostat is brain permeable and can prevent the formation of brain metastases by 62%. Its mechanism of action involves the induction of DNA double-strand breaks, suggesting rational combinations with DNA active drugs or radiation. Experiment Overall Design: We performed gene expression profiling on metastases from vehicle- or vorinostat-treated mice to determine if alterations in gene expression were observable that were consistent with the phenotypes observed. Brain metastases from five vehicle-treated mice and six 150 mg/kg vorinostat-treated mice were procured by laser capture microdissection. RNA was extracted from the captured tumor cells from each brain and two rounds of linear amplification was done. The amplified RNA from each mouse was processed separately through microarray hybridization and analysis.

Project description:The identification of recurrent somatic mutations in genes encoding epigenetic enzymes, coupled with biochemical studies demonstrating aberrant recruitment of epigenetic enzymes such as histone deacetylases (HDACs) and histone methyltransferases (HMTs) to promoter regions through association with oncogenic fusion proteins such as PML-RARM-NM-1 and AML1-ETO has provided a strong rationale for the development compounds that target the epigenome for the treatment of cancer. HDAC inhibitors (HDACi) are potent inducers of tumor cell apoptosis but it remains unclear why tumor cells are selectively sensitive to HDACi-induced cell death. Herein we assessed the biological and molecular responses of normal and transformed cells to the FDA-approved HDACi vorinostat. Both HDACi selectively killed cells of diverse tissue origin that had been transformed through the serial introduction of different oncogenes. Time course microarray expression profiling revealed that normal and transformed cells transcriptionally responded to vorinostat treatment. Over 4200 genes responded differently to vorinostat in normal and transformed cells and gene ontology and pathway analyses identified a tumor-cell-selective pro-apoptotic gene-expression signature that consisted of BCL2 family genes. In particular, HDACi induced tumor cell-selective upregulation of the pro-apoptotic gene BMF and downregulation of the pro-survival gene BCL2A1 encoding BFL-1. Maintenance of BFL-1 levels in transformed cells through forced expression conferred vorinostat resistance indicating that specific and selective engagement of the intrinsic apoptosis pathways underlies the tumor cell-selective apoptotic activities of these agents. The ability of HDACi to affect the growth and survival of tumor cells whilst leaving normal cells relatively unharmed is fundamental to their successful clinical application. This study provides new insight into the transcriptional effects of HDACi in human donor-matched normal and transformed cells, and identifies molecules and pathways that could underpin the tumor-selective cytotoxic activity of these compounds. Whole genome expression profiling was performed for vorinostat-treated samples and control samples (DMSO vehicle control). Fourteen samples were included in this study. Each sample has three biological replicates, making forty-two arrays in total.

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The Pelvic Radiation and Vorinostat (PRAVO) Study - Histone Deacetylase Inhibitor Activity

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