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

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. Overall design: 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).

本研究旨在阐明组蛋白去乙酰化酶抑制剂伏立诺他（vorinostat）的分子作用机制。
在PRAVO I期临床试验中，针对拟接受盆腔姑息放射治疗（分割剂量3 Gy，总剂量30 Gy）治疗胃肠道癌的患者，按序纳入4个递增剂量的伏立诺他给药组，初始给药剂量为每日100 mg，剂量递增梯度为100 mg。本研究的终点指标包括治疗安全性与耐受性、肿瘤应答情况以及伏立诺他的生物学活性。为鉴定伏立诺他作用的生物标志物，本研究采用代表暴露于伏立诺他的正常组织的外周血单个核细胞（peripheral blood mononuclear cells）。样本共采集3份：1份基线样本与2份治疗期间样本，采样时间点的选择基于本团队此前针对伏立诺他处理的结直肠癌实验模型的研究数据，该数据显示，药物暴露后2~3小时肿瘤组蛋白乙酰化水平达到峰值，24小时后恢复至基线水平。在PRAVO研究的患者中，伏立诺他给药3小时后可观察到肿瘤组蛋白高度乙酰化。
整体研究设计：本研究共纳入17例PRAVO研究患者，其中14例获取了完整的3份样本：伏立诺他治疗开始前采集的基线样本（T0），以及患者接受当日末次伏立诺他给药后2小时、24小时采集的2份治疗期间样本（T2与T24）。伏立诺他的给药剂量梯度为100 mg（D100）、200 mg（D200）、300 mg（D300）与400 mg（D400）。