Clinical Trial: Preoperative Bexarotene Treatment for Cushing's Disease
Study Status: Withdrawn
Recruit Status: Unknown status
Study Type: Interventional
Official Title: Preoperative Bexarotene Treatment for Cushing's Disease
Brief Summary: The objective of this pilot study is to establish the safety and tolerability of short-term therapy with bexarotene in patient's with Cushing's disease, and study the clinical, biochemical, and cellular effects of a preoperative five-day course of bexarotene in these patients before undergoing transsphenoidal surgery.
Detailed Summary:
Cushing's disease refers to a condition of glucocorticoid excess caused by an adrenocorticotropic hormone (ACTH) producing pituitary tumor, which account for 10-15% of all pituitary tumors. The majority of corticotroph tumors are microadenomas at the time of diagnosis, and accurate surgical and histologic identification of these tumors can be challenging. ACTH is produced in corticotroph cells within the anterior pituitary via the precursor pro-opiomelanocortin (POMC). In both physiologic and pathologic conditions the promoter for POMC is regulated by multiple transcription factors which include AP-1 and Nurr77. Retinoic acid has been shown to inhibit activation of the POMC promoter in corticotroph tumor cell culture via disruption of Nurr77 transcriptional activity. The expression of the orphan nuclear receptor termed chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI) antagonizes retinoic acid signaling, and has been reported to be present in normal corticotroph cells, but lacking in adenomatous corticotroph cells in tissue culture studies. Through the retrospective analysis of 34 human corticotroph tumors we have demonstrated a consistent lack of COUP-TFI in 100% of the microadenomas that were not visible, or measured less than 5 millimeters by preoperative MRI. In total, 85% of all tumors studied showed absence of COUP-TFI. Based on in vitro data from rat and human corticotroph tumors, cells lacking COUP-TFI are vulnerable to retinoid-induced cell death via Nurr77-mediated apoptosis, an effect that is reversed by COUP-TFI gene transfection. In 2006, Castillo et al. published the results of a six-month trial which randomized 44 dogs with Cushing's disease to an RXR agonist (9-cis retinoic acid), or to ketoconazole. RXR agonist therapy outperformed ketoconazole for all endpoints, resulting in normalization of ACTH and cortisol levels in 100% of subjects that completed the study, and improved morbidity
Sponsor: University of Virginia
Current Primary Outcome:
- diurnal plasma ACTH [ Time Frame: Days 1- 5 ]
- cortisol levels [ Time Frame: Days 1-5 ]
- Adverse events [ Time Frame: Days 1-5 and day two post-op ]
Original Primary Outcome: Same as current
Current Secondary Outcome: clinical outcomes [ Time Frame: Day 1-5, then at month 6 and 12, then every 12 months ]
Original Secondary Outcome: Same as current
Information By: University of Virginia
Dates:
Date Received: February 16, 2009
Date Started: November 2008
Date Completion: December 2011
Last Updated: May 26, 2011
Last Verified: May 2011
