Journal Article

Treatment of Cushing Disease With Pituitary-Targeting Seliciclib

Liu, Ning-Ai, Swerdloff, Ronald S, Barkhoudarian, Garni, Mirocha, James, Desai, Manish, Ben-Shlomo, Anat, Kelly, Daniel, Tighiouart, Mourad, Lu, Lin, Stolyarov, Yana, Melmed, Shlomo, Heaney, Anthony P, Wang, Christina, Yuen, Kevin, Mamelak, Adam N, Noureddin, Mazen, Carmichael, John D

2023

Overview

Abstract Context Preclinical studies show seliciclib (R-roscovitine) suppresses neoplastic corticotroph proliferation and pituitary adrenocorticotrophic hormone (ACTH) production. Objective To evaluate seliciclib as an effective pituitary-targeting treatment for patients with Cushing disease (CD). Methods 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. Results 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. Conclusion 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.

• Publisher: Oxford University Press
• Subject: ACTH / Adrenocorticotropic Hormone / Adult / Anemia / Cabergoline / Clinical / Clinical trials / Corticosteroids / Creatinine / Cushing syndrome / Cushing's disease / Development and progression / Enzymes / Humans / Hydrocortisone / Liver / Medical research / Medicine, Experimental / Nervous system diseases / Pituitary / Pituitary (anterior) / Pituitary ACTH Hypersecretion - drug therapy / Prospective Studies / Roscovitine / Roscovitine - therapeutic use / Toxicity