New molecular targeted therapies in thyroid cancer.

ABSTRACT

Carcinoma of the thyroid gland is the most common malignancy of the endocrine system. Differentiated tumors are often curable with surgical resection and radioactive iodine. A small percentage of such patients, however, do not undergo remission and need new therapeutic approaches. Both anaplastic and medullary thyroid carcinomas exhibit aggressive behavior and are usually resistant to current therapeutic modalities. Thyroid carcinoma represents a fascinating model and a particularly promising paradigm for targeted therapy because some of the key oncogenic events are activating mutations of genes coding for tyrosine kinases, and these occur early in cancer development. A prototype is the RET proto-oncogene, a receptor tyrosine kinase, which is a key regulator of development and a 'hotspot' for oncogenic mutations. Mutations in the RET proto-oncogene have been identified as causative for papillary carcinoma and familial medullary thyroid carcinoma, making it an attractive target for selective inhibition in these subtypes. ZD 6474 has shown promising activity in preclinical models against RET kinase, and its contemporary inhibition of vascular endothelial growth factor and epidermal growth factor pathways renders it a very attractive drug for clinical trials in thyroid cancer. Activating point mutation of B-RAF can occur early in the development of papillary carcinoma. Moreover, papillary carcinomas with these mutations have more aggressive properties and are diagnosed more often at an advanced stage. Clinical evaluation of B-RAF-targeting drugs is undergoing and trials in thyroid cancer are planned. Agents that restore radioiodine uptake, such as histone deacetylase inhibitors and retinoids, represent another exciting field in new drug development in thyroid cancer.