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.
| Araki, Takako; Liu, Ning-Ai (2018) Cell Cycle Regulators and Lineage-Specific Therapeutic Targets for Cushing Disease. Front Endocrinol (Lausanne) 9:444 |
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| Araki, Takako; Liu, Xiaohai; Kameda, Hiraku et al. (2017) EGFR Induces E2F1-Mediated Corticotroph Tumorigenesis. J Endocr Soc 1:127-143 |
| Recouvreux, M Victoria; Wu, J Boyang; Gao, Allen C et al. (2017) Androgen Receptor Regulation of Local Growth Hormone in Prostate Cancer Cells. Endocrinology 158:2255-2268 |
| Araki, Takako; Liu, Ning-Ai; Tone, Yukiko et al. (2016) E2F1-mediated human POMC expression in ectopic Cushing's syndrome. Endocr Relat Cancer 23:857-870 |
| Chesnokova, Vera; Zonis, Svetlana; Zhou, Cuiqi et al. (2016) Growth hormone is permissive for neoplastic colon growth. Proc Natl Acad Sci U S A 113:E3250-9 |
| Melmed, Shlomo (2016) Pituitary Medicine From Discovery to Patient-Focused Outcomes. J Clin Endocrinol Metab 101:769-77 |
| Rogatko, André; Cook-Wiens, Galen; Tighiouart, Mourad et al. (2015) Escalation with Overdose Control is More Efficient and Safer than Accelerated Titration for Dose Finding. Entropy (Basel) 17:5288-5303 |
| Melmed, Shlomo (2015) Pituitary tumors. Endocrinol Metab Clin North Am 44:1-9 |
| Melmed, Shlomo (2015) Fertility and fragrance: another cause of Kallmann syndrome. J Clin Invest 125:2275-8 |
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