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Treatment of Cushing Disease With Pituitary-Targeting Seliciclib.
- Source :
- Journal of Clinical Endocrinology & Metabolism; Mar2023, Vol. 108 Issue 3, p726-735, 10p
- Publication Year :
- 2023
-
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 liverrelated 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. [ABSTRACT FROM AUTHOR]
- Subjects :
- CUSHING'S syndrome
ADRENOCORTICOTROPIC hormone
PITUITARY diseases
Subjects
Details
- Language :
- English
- ISSN :
- 0021972X
- Volume :
- 108
- Issue :
- 3
- Database :
- Complementary Index
- Journal :
- Journal of Clinical Endocrinology & Metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 162018234
- Full Text :
- https://doi.org/10.1210/clinem/dgac588