Our discovery from innovative laboratory research has led to the identification of R-roscovitine, a selective CDK inhibitor with dual effect suppressing both cell proliferation and ACTH production in pituitary corticotroph tumors. We now propose a pilot, proof of concept phase II clinical trial to treat with R-roscovitine of patiens with corticotroph tumors (Cushing disease), who are recruited from the Pituitary Center at Cedars-Sinai Medical Center, to determine if R-roscovitine can safely normalize urinary free cortisol levels by reducing pituitary corticotroph tumor ACTH production. R-roscovitine has been undergoing phase I and II clinical trials for several malignancies, and, if effective for corticotrph tumors, its oral dosing route and relatively mild side effects make daily long-term treatment of Cushing disease feasible. Our study will explore a novel intervention for much needed pharmaco-therapeutic strategies directly targeting pituitary corticotroph tumors, one of the most challenging human neuroendocrine diseases.
We have identified a small molecule CDK2/cyclin E inhibitor, R-roscovitine, which has a dual action suppressing both cell proliferation and ACTH production in pituitary corticotroph tumors. By performing the proposed pilot, proof of concept phase II clinical trial with R-roscovitine, we will test a new and unique intervention directly targeting corticotroph tumors in patients with Cushing disease. Data collected from the proposed study will serve as a basis of developing a future R01 grant application for a full-scale clinical trial.