Treatment of Cushing's Disease with Pituitary-Targeting Seliciclib.
Publication Title
The Journal of clinical endocrinology and metabolism
Document Type
Article
Publication Date
10-10-2022
Keywords
california; psjhc; santa monica
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's disease (CD).
DESIGN: Two prospective, open-label, phase 2 trials.
SETTING: Tertiary referral pituitary center.
PATIENTS: Adult patients with de novo, persistent, or recurrent CD.
INTERVENTION: Oral seliciclib 400 mg twice daily for 4 consecutive days each week for 4 weeks.
MAIN OUTCOME MEASURES: Primary endpoint in the proof-of-concept single-center study was normalization of 24-hour urinary free cortisol (UFC; ≤ 50 µg/24 h) 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 h at baseline to 131.3 ± 114.3 µg/24 h by study end. Longitudinal model showed significant UFC reductions from baseline to each treatment week. Three patients achieved ≥50% UFC reduction (range, 55% to 75%), and 2 patients exhibited 48% reduction; but 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.
CONCLUSIONS: 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.
Clinical Institute
Neurosciences (Brain & Spine)
Specialty/Research Institute
Neurosciences
