Treatment of Cushing's Disease with Pituitary-Targeting Seliciclib.
The Journal of clinical endocrinology and metabolism
california; psjhc; santa monica
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.
Neurosciences (Brain & Spine)
Liu, Ning Ai; Ben-Shlomo, Anat; Carmichael, John D; Wang, Christina; Swerdloff, Ronald S; Heaney, Anthony P; Barkhoudarian, Garni; Kelly, Daniel; Noureddin, Mazen; Lu, Lin; Desai, Manish; Stolyarov, Yana; Yuen, Kevin; Mamelak, Adam N; Mirocha, James; Tighiouart, Mourad; and Melmed, Shlomo, "Treatment of Cushing's Disease with Pituitary-Targeting Seliciclib." (2022). Articles, Abstracts, and Reports. 6666.