Preoperative Bexarotene Treatment for Cushing's Disease

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 and mortality. All of the dogs treated with the RXR agonist remained in remission
for the duration of the 6 to 12 month post-treatment followup.

This pilot study will involve inpatient admission to our General Clinical Research Center
for 5 days prior to scheduled transsphenoidal surgery. During the five days of the study
each individual will receive the RXR-agonist bexarotene at the FDA approved dose of 300
mg/m2/day. Clinical signs and symptoms of acute adrenal insufficiency will be monitored
routinely throughout each 24-hour period. Baseline and twice-daily biochemical analysis for
ACTH and cortisol will be performed. 24-hour urine collection for cortisol will be obtained
pre-treatment and in the last 24-hours of treatment. Laboratory safety analysis will include
serial comprehensive metabolic panels to monitor liver and kidney function, complete blood
count to monitor for neutropenia, as well as thyroid function studies to monitor for central
hypothyroidism which can develop with therapy.

Inclusion Criteria:

- Age 18-65

- Clinical and biochemical diagnosis of Cushing's disease as established by clinical
history, physical exam, and definitive biochemical testing:

1. Persistent hypercortisolemia established by 24 hour urine free cortisol
measurements

2. Confirmation of pituitary-dependent hypercortisolemia 1. ACTH levels normal or
elevated, and if clinically necessary, one of the following:

1. Suppression of 24 hour urine free cortisol with either the 48-hour dexamethasone
suppression test, or suppression of serum cortisol after an overnight high-dose
(8 mg) dexamethasone suppression test -OR-

2. Inferior Petrosal Sinus Sampling (IPSS) study

- Pituitary MRI performed within three months of enrollment

- Health status deemed appropriate for transsphenoidal surgery by the neurosurgical
preoperative evaluation at the University of Virginia Pituitary Clinic

Exclusion Criteria:

- Age less than 18 or greater than 65

- Pregnant or nursing mothers

- Previous surgical, medical, or radiation therapy involving the pituitary fossa

- History of malignancy, solid or hematogenous

- History of intracranial disease, injury or intracranial surgical procedure

- Renal impairment with a GFR estimated at < 60 mL/min/1.73 m2

- History of liver disease, or baseline liver transaminase levels >50% above the upper
limit of normal

- Fasting Triglycerides > 200 mg/dL

- History of pancreatitis

- Pituitary macroadenoma (> 1 cm) as measured by MRI performed within 3 months of
enrollment

- Previous treatment for Cushing's disease including surgery, radiation, or medical
therapy:

1. Ketoconazole

2. Metyrapone

3. Aminoglutethimide

4. Mitotane

- Oral or systemic glucocorticoid use in the last six months

- Intraarticular injection of glucocorticoids in the last year

- Current use of Ketoconazole, itraconazole, erythromycin, gemfibrozil, grapefruit
juice, or other inhibitors of cytochrome P450 3A4

- Any disability or cognitive, educational, or language barriers which would inhibit
the subject's ability to adequately understand the verbal and written material in the
consent process despite the use of standard language translation services available
through our clinic