Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Pituitary Center, Department of Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA.
J Clin Endocrinol Metab. 2023 Feb 15;108(3):726-735. doi: 10.1210/clinem/dgac588.
Preclinical studies show seliciclib (R-roscovitine) suppresses neoplastic corticotroph proliferation and pituitary adrenocorticotrophic hormone (ACTH) production.
To evaluate seliciclib as an effective pituitary-targeting treatment for patients with Cushing disease (CD).
Two prospective, open-label, phase 2 trials, conducted at a tertiary referral pituitary center, included adult patients with de novo, persistent, or recurrent CD who received oral seliciclib 400 mg twice daily for 4 consecutive days each week for 4 weeks. The primary endpoint in the proof-of-concept single-center study was normalization of 24-hour urinary free cortisol (UFC; ≤ 50 µg/24 hours) at study end; in the pilot multicenter study, primary endpoint was UFC normalization or ≥ 50% reduction in UFC from baseline to study end.
Sixteen patients were consented and 9 were treated. Mean UFC decreased by 42%, from 226.4 ± 140.3 µg/24 hours at baseline to 131.3 ± 114.3 µg/24 hours by study end. Longitudinal model showed significant UFC reductions from baseline to each treatment week. Three patients achieved ≥ 50% UFC reduction (range, 55%-75%), and 2 patients exhibited 48% reduction; none achieved UFC normalization. Plasma ACTH decreased by 19% (P = 0.01) in patients who achieved ≥ 48% UFC reduction. Three patients developed grade ≤ 2 elevated liver enzymes, anemia, and/or elevated creatinine, which resolved with dose interruption/reduction. Two patients developed grade 4 liver-related serious adverse events that resolved within 4 weeks of seliciclib discontinuation.
Seliciclib may directly target pituitary corticotrophs in CD and reverse hypercortisolism. Potential liver toxicity of seliciclib resolves with treatment withdrawal. The lowest effective dose requires further determination.
临床前研究表明，seliciclib（R-roscovitine）可抑制肿瘤性促皮质激素细胞的增殖和垂体促肾上腺皮质激素（ACTH）的产生。
评估 seliciclib 作为一种有效的针对垂体的治疗方法，用于治疗库欣病（CD）患者。
两项前瞻性、开放标签、2 期临床试验在一家三级转诊垂体中心进行，纳入了新发、持续或复发的 CD 成年患者，这些患者接受口服 seliciclib，每日两次，每次 400mg，连续 4 天，每周连续 4 周。单中心概念验证研究的主要终点是研究结束时 24 小时尿游离皮质醇（UFC；≤50μg/24 小时）正常化；在试点多中心研究中，主要终点是 UFC 正常化或从基线到研究结束时 UFC 降低≥50%。
共同意了 16 名患者，并对其中 9 名患者进行了治疗。UFC 平均降低了 42%，从基线时的 226.4±140.3μg/24 小时降至研究结束时的 131.3±114.3μg/24 小时。纵向模型显示，从基线到每个治疗周，UFC 均有显著降低。3 名患者的 UFC 降低≥50%（范围 55%-75%），2 名患者的 UFC 降低 48%；没有患者达到 UFC 正常化。在 UFC 降低≥48%的患者中，血浆 ACTH 降低了 19%（P=0.01）。3 名患者出现了≤2 级的肝酶升高、贫血和/或肌酐升高，通过中断/减少剂量得到了缓解。2 名患者出现了 4 级与肝相关的严重不良事件，但在 seliciclib 停药后 4 周内得到了缓解。
seliciclib 可能直接靶向 CD 中的垂体促皮质激素细胞，并逆转皮质醇增多症。seliciclib 的潜在肝毒性在停药后可得到缓解。还需要进一步确定最低有效剂量。
