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Seliciclib for the Treatment of Cushing’s Disease Targeting Pituitary

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The following is a summary of “Treatment of Cushing Disease With Pituitary-Targeting Seliciclib,” published in the March 2023 issue of Endocrinology & Metabolism by Liu, et al.

Seliciclib (R-roscovitine) has been shown in preclinical studies to inhibit neoplastic corticotroph proliferation and the production of adrenocorticotropic hormone (ACTH) in the pituitary gland. Therefore, for a study, researchers sought to investigate the effectiveness of seliciclib as a pituitary-targeting treatment for patients with Cushing’s disease (CD).

Two prospective, open-label, phase 2 trials were conducted at a tertiary referral pituitary center. Adult patients with de novo, persistent, or recurrent CD received oral seliciclib 400 mg twice daily for four consecutive days each week for four weeks. The primary endpoint in the single-center study was normalization of 24-hour urinary free cortisol (UFC; ≤ 50 µg/24 hours) at the end of the study, and in the multicenter study, the primary endpoint was UFC normalization or a ≥ 50% reduction in UFC from baseline to the end of the study.

Of the 16 patients who consented, 9 were treated with seliciclib. The mean UFC decreased by 42% from 226.4 ± 140.3 µg/24 hours at baseline to 131.3 ± 114.3 µg/24 hours at the end of the study. The longitudinal model showed significant reductions in UFC from baseline to each treatment week. Three patients achieved a ≥ 50% reduction in UFC (range, 55%-75%), and two exhibited a 48% reduction; none achieved UFC normalization. Plasma ACTH decreased by 19% (P = 0.01) in patients with ≥48% UFC reduction. Three patients developed grade ≤ 2 elevated liver enzymes, anemia, and/or elevated creatinine, resolved with dose interruption/reduction. Two patients developed grade 4 liver-related serious adverse events that resolved within four weeks of seliciclib discontinuation.

The results suggested that seliciclib may target pituitary corticotrophs in CD and reverse hypercortisolism. Although potential liver toxicity of seliciclib resolves with treatment withdrawal, a further determination is required to establish the lowest effective dose.

Source: academic.oup.com/jcem/article-abstract/108/3/726/6754906?redirectedFrom=fulltext

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