Redifferentiation Therapy in Advanced Thyroid Cancer

Thyroid cancer is a relatively common malignancy with an estimated prevalence of 250,000 in the U.S. A minority of patients have poorly differentiated thyroid carcinoma that is unresponsive to radioiodine therapy. Redifferentiation agents that 'reprogram' these tumors to concentrate radioiodine would be of great value in treating patients with advanced thyroid cancer. The retinoid isotretinoin is the most extensively studied of these agents. It appears that 20-40% of patients respond to isotretinoin treatment by concentration of radioiodine in metastatic tumors, but the clinical utility of this redifferentiation is still unclear. In vitro studies suggest that the retinoid receptors (RARbeta and RXRgamma) are required for this effect. Abnormal DNA methylation may be an early event in thyroid tumorigenesis and methylation of the sodium iodide symporter (NIS) may play a role in the loss of iodine concentration in these tumors. Inhibitors of methylation (5-azacytidine, phenylacetate and sodium butyrate) have been shown to increase NIS expression and iodine uptake in cell culture models, but published trials in humans are not yet available. Histone acetylation is required for efficient transcription of genes necessary for differentiated function. Proteins that cause histone deacetylation inhibit gene transcription and differentiated function. Inhibitors of histone deacetylation (depsipeptide, trichostatin A) have been shown to increase NIS expression and iodine uptake in poorly differentiated and undifferentiated cell lines. Phase II human trials are currently underway for depsipeptide. Finally, commonly used agents such as thiazolidinediones (diabetes) and HMG-CoA reductase inhibitors (hypercholesterolemia) have shown promise in preliminary in vitro studies in advanced thyroid cancer cell lines. Development of these and other novel agents for the treatment of advanced thyroid cancer is critical for us to treat an uncommon progression of a common malignancy.