ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, MA 02139, USA.
Cancer Chemother Pharmacol. 2012 May;69(5):1369-77. doi: 10.1007/s00280-011-1813-7. Epub 2012 Jan 10.
As part of a phase 1 dose-escalation trial, the pharmacodynamic activity of the mammalian target of rapamycin (mTOR) inhibitor ridaforolimus was assessed in multiple tissues by measuring levels of phosphorylated 4E binding protein-1 (p-4E-BP1) or S6, two downstream markers of mTOR activity.
32 patients (pts) were dosed intravenously with ridaforolimus once daily for 5 consecutive days (QD × 5) every 2 weeks. The pharmacodynamic activity of ridaforolimus was assessed in peripheral blood mononuclear cells (PBMCs; 32 pts), skin (28 pts), and tumor specimens (3 pts) collected before and after dosing by measuring levels of p-4E-BP1 by immunoblot analysis or pS6 by immunohistochemistry. Levels of these markers were assessed in up to 19, 5, and 2 pre- and post-dose time points in PBMC, skin, and tumor specimens, respectively.
In preclinical models, ridaforolimus induced a dose-dependent inhibition of p-4E-BP1 in PBMCs that was associated with antitumor activity. Rapid and potent inhibition of mTOR was observed in PBMCs from all 32 pts dosed, with a median level of inhibition of 96% observed within 1 h after the first dose. Inhibition of mTOR (>90%) was sustained during the entire QD × 5 dosing period, and substantial inhibition was still observed after the 9-day holiday between dosing courses. Evidence of mTOR inhibition was also obtained in skin in pts from all dose cohorts, although it did not persist through the break between courses. After two to three doses of ridaforolimus, inhibition of mTOR was detected in the tumor from one of three pts analyzed.
Ridaforolimus was shown to inhibit its intended target, mTOR, in PBMCs, skin, and tumors. In PBMCs and skin, inhibition was observed at all dose levels tested, thus supporting but not driving the selection of a recommended phase 2 dose.
在一项 1 期剂量递增试验中，通过测量哺乳动物雷帕霉素靶蛋白（mTOR）活性的两个下游标志物磷酸化 4E 结合蛋白-1（p-4E-BP1）或 S6 的水平，评估 mTOR 抑制剂 ridaforolimus 在多种组织中的药效学活性。
32 例患者（pts）每 2 周静脉给予 ridaforolimus 一次，连续 5 天，每天 1 次（QD×5）。通过免疫印迹分析测量外周血单个核细胞（PBMC）（32 例 pts）、皮肤（28 例 pts）和肿瘤标本（3 例 pts）中 p-4E-BP1 的水平，或通过免疫组化测量 pS6 的水平，评估给药前后 ridaforolimus 的药效学活性。分别在 PBMC、皮肤和肿瘤标本中最多评估 19、5 和 2 个给药前和给药后时间点的这些标志物水平。
在临床前模型中，ridaforolimus 诱导 PBMC 中 p-4E-BP1 的剂量依赖性抑制，这与抗肿瘤活性相关。所有 32 例接受治疗的患者的 PBMC 中均观察到快速且强效的 mTOR 抑制，首次给药后 1 小时内观察到中位抑制率为 96%。在整个 QD×5 给药期间，mTOR 抑制持续，在两个疗程之间的 9 天停药期后仍观察到大量抑制。在所有剂量组的患者皮肤中也观察到 mTOR 抑制的证据，尽管它在疗程之间没有持续。在分析的 3 例患者中的 1 例肿瘤中，在接受 ridaforolimus 两到三剂后检测到 mTOR 抑制。
ridaforolimus 被证明能抑制其预期的靶标 mTOR 在 PBMCs、皮肤和肿瘤中的活性。在 PBMCs 和皮肤中，在所有测试的剂量水平均观察到抑制，因此支持但不驱动选择推荐的 2 期剂量。
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