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by Anthony P. Heaney MD, PhD
Summer, 2004
Cushing's disease is caused by an ACTH-secreting pituitary tumor, 90% of which are < 1 cm diameter. Despite their small size, these microadenomas cause elevated, non-suppressible ACTH levels, leading to adrenal-derived cortisol hypersecretion and a myriad of disabling and sometimes life-threatening symptoms including abnormal fat deposition, skin thinning, psychological disturbances, hypertension, diabetes, osteoporosis and muscle weakness.
Unless treated, Cushing's disease is associated with high morbidity and ultimately mortality. In experienced specialized centers, the majority of ACTH-secreting microadenomas can be successfully resected by transsphenoidal pituitary surgery, but surgical "cure" rates for larger ACTH-secreting pituitary tumors are achieved less often. Post-surgical persistence of ACTH hypersecretion may require pituitary-directed radiation, effects of which may not be manifest for many years, and like extensive surgical pituitary tumor resection, ultimately leads to partial- or total hypopituitarism in a large number of cases. Although hypercortisolism may be completely resolved by adrenalectomy, this procedure does not suppress, and may act as a stimulus to pituitary tumor growth, and is associated with other co-morbidity.
While some GH (growth hormone) and PRL (prolactin) secreting pituitary tumors require surgery, often times these tumors can be treated by drug therapy alone. The drug therapy used, dopamine agonists and somatostatin analogs, effectively suppress PRL and GH hypersecretion respectively and control tumor growth. No similarly effective drug therapies for ACTH-secreting pituitary tumors currently exist, and surgical excision is currently the only effective treatment.
The therapeutic goal in the treatment of patients with Cushing's disease is normalization of plasma ACTH, and serum cortisol values, tumor shrinkage, and preservation of anterior pituitary function. Current drug-based therapy for Cushing's Disease includes neuromodulator drugs that act at the hypothalamic-pituitary level, such as serotonin antagonists (cyproheptadine, ketanserin, retanserin) dopamine agonists (bromocriptine, cabergoline), GABA agonists (sodium valproate), and somatostatin receptor ligands (octreotide). These drug-based treatments for Cushing's disease, have all been reported to work occasionally, however, they do not impact on pituitary tumor growth, and have rarely shown real clinical efficacy when used as sole treatment. Ketoconazole and other drugs that act on the adrenal glands to decrease steroid synthesis, can lower cortisol levels, but do not decrease tumor size and are rarely effective for long-term control of hypercortisolism. Thus, current drug therapy is largely reserved for pre-operative treatment of severe hypercortisolism, for patients awaiting pituitary radiation-induced cortisol suppression, in cases where the tumor cannot be located, or whenever a definitive treatment is delayed, perhaps due to intercurrent illness.
Current Laboratory Research
To identify potential drug targets, initial studies are often performed on tumor cells grown in dishes in the laboratory. Human pituitary tumor cells are difficult to grow in dishes, thus mouse cells, which grow more readily, are often used. Our laboratory has been experimenting with both ACTH secreting human and mouse cells grown in dishes. We have recently found that drugs that bind to the peroxisome-proliferator activating receptor-gamma (PPAR- g) dramatically influence ACTH secretion and cell growth, thus these drugs may lead to novel therapeutic approaches in Cushing's disease.
Normal cells tightly control cell growth and ACTH secretion by what genes are tuned on or off and how much of a gene product is present (expressed). Some gene products are often over-expressed in tumor cells when compared to normal cells. PPAR-g is a member of the nuclear receptor superfamily, like the better-known estrogen receptor, and regulates expression of other genes. Compounds that bind to PPAR-g and mediate its actions (called ligands) include the thiazolidinedione compounds (TZD's) that are commonly employed in the treatment of type II diabetes. The PPAR-g is expressed at high levels in several cancers including breast, prostate and colon cancer, and treatment of cancer cells with PPAR-g ligands, such as TZD's, inhibits prostate and colon tumor cell growth.
We recently demonstrated that PPAR-g expression is only found in the ACTH-secreting cells in the normal human pituitary, and is abundantly expressed in ACTH secreting tumors surgically removed from patients with Cushing's disease. When human and mouse ACTH secreting tumors grown in dishes were treated with PPAR-g drugs such as the TZD rosiglitazone , growth of the tumor cells was reduced. In addition, the TZD-treatment killed the ACTH secreting tumor cells and inhibited ACTH secretion. We also examined the effects of the TZD-drug treatment on ACTH secreting pituitary tumors after they were inoculated subcutaneously in mice. Animals that were treated with high doses of rosiglitazone intermixed in their food developed smaller tumors and ACTH and corticosterone levels were dramatically lower compared to the mice that just received regular food.
Potential Clinical Utility in Humans
These findings suggest a potential role for these TZD drugs in the management of human pituitary ACTH secreting tumors, as in addition to exerting inhibitory effects on pituitary tumor growth, they also inhibit tumor ACTH synthesis and secretion. Rosiglitazone, a potent thiazolidinedione oral antidiabetic agent, has been extensively and safely used to treat diabetes in humans. Thus far, we have treated three patients with failed pituitary surgery for Cushing's Disease with standard doses of rosiglitazone. A favorable response was observed in two out of the three patients. While these clinical findings are very preliminary, combined with the abundant and selective PPAR-g expression in ACTH secreting pituitary tumors, they support evaluation of the potential use of TZD's in treating patients with Cushing's disease in controlled clinical trials. A clinical trial protocol is currently under development at Cedars Sinai.
Editor's Note: Anthony P. Heaney MD, PhD is Medical Director of the Carcinoid and Neuroendocrine Tumor Center and Director of the Endocrine Fellowship Program at Cedars-Sinai. Dr. Heaney is also Associate Professor of Endocrinology at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA). Dr. Heaney's primary areas of research interest involve the genesis of pituitary tumors and innovative treatments for Cushing's syndrome. |
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