Evolving strategies for targeted cancer therapy--past, present, and future.

Medullary thyroid carcinoma occurs most often as a sporadic malignancy, although in approximately 30% of cases, it occurs as part of the multiple endocrine neoplasia type 2 (MEN2) syndromes MEN2A and MEN2B or the related disease, familial medullary thyroid carcinoma. These three syndromes, inherited as autosomal dominant traits, are clinically characterized by near complete penetrance but variable expressivity. The thyroid malignancy is present in virtually all patients with MEN2A, MEN2B, and familial medullary thyroid carcinoma, and it is the most common cause of death in affected patients. Medullary thyroid carcinoma cells secrete the hormone calcitonin, and elevated plasma levels of this polypeptide, either basally or following provocation with intravenous calcium and pentagastrin, indicate the presence of medullary thyroid carcinoma, even though the tumor may not be clinically evident. The test is especially useful for evaluating patients after removal of the thyroid gland. Recently, it was discovered that mutations in the RET protooncogene are causative of MEN2A, MEN2B, and familial medullary thyroid carcinoma (1–3). Subsequently, it was found that approximately 30% of patients with sporadic medullary thyroid carcinoma have a RET mutation in the medullary thyroid carcinoma cells but not in germline DNA (4). Furthermore, in patients with papillary thyroid carcinoma, the most common endocrine malignancy, the RET gene is activated secondary to a chromosomal rearrangement, resulting in fusion of the portion of the RET gene encoding tyrosine kinase to an upstream region derived from one of several genes expressed in normal thyroid follicular cells (5). RET expression is driven by the promoters of the fused genes, resulting in constitutive activation of the kinase. Patients with medullary thyroid carcinoma are cured only by total thyroidectomy, performed when the disease is confined to the thyroid gland. Since the malignancy is not responsive to standard chemotherapeutic regimens or to conventional doses of external beam radiotherapy, early diagnosis and treatment are essential. Patients who seek medical advice because of a thyroid nodule are usually incurable because the cancer has already metastasized to regional lymph nodes or distant sites. Conversely, kindred members at direct risk for MEN2A, MEN2B, or familial medullary thyroid carcinoma can be identified as having inherited a mutated RET allele by direct DNA analysis early in life. Total thyroidectomy, performed prior to clinical or biochemical evidence of medullary thyroid carcinoma, is curative in a high percentage of patients. Papillary thyroid carcinoma is also treated by thyroidectomy; however, most patients with persistent or recurrent distant disease can be effectively treated with radioactive iodine. If this treatment fails, patients may succumb to disease. Thus, for many patients with hereditary or sporadic medullary thyroid carcinoma, and for some patients with papillary thyroid carcinoma who are not cured by total thyroidectomy and other adjuvant therapies, there is no effective treatment. In this issue of the Journal, Cuccuru et al. (6) report antitumor activity of the RET inhibitor, RPI-1, in MEN2A-associated medullary thyroid carcinoma. This activity coincides with the ability of the drug to inhibit tumor cell proliferation as well as anchorage-independent growth and reflects the inhibition of the tyrosine kinase activity of the receptor. Similarly, Carlomagno et al. (7) earlier reported that the quinazoline ZD6474 was a potent inhibitor of RET oncoproteins, which exerted powerful growthinhibitory effects on thyroid carcinoma cell lines with RET/ papillary thyroid carcinoma rearrangements. ZD6474 also inhibited angiogenesis and thus exhibited a dual antitumor effect. These two studies, based on an understanding of the oncogenic process, support the “targeted therapy” approach for patients with diseases characterized by RET activation and offer the possibility of a successful interventional therapy when conventional pharmacologic and radiotherapeutic regimens have failed. A major success story in the development of targeted therapeutics is the use of imatinib mesylate (Gleevec STI571), which inhibits Abl tyrosine kinase (8–12), for treating chronic myelocytic leukemia. This successful therapy also emphasizes the challenges of treating advanced-stage disease, because tumors that are initially sensitive to the action of a given drug often develop resistance to that drug over time. Thus, understanding the complexity of the oncogenic process to then design and apply additional therapies will be critical to long-term success. In the case of RET, one approach might rely on the development of multiple targeted drugs as described by Cuccuru (6) and Carlomagno (7). Tumors that develop resistance to one agent, particularly in those instances of RET mutations that block drug interaction, may retain sensitivity to another drug. A second approach to managing resistance might take advantage of combinational therapy that targets multiple steps in the oncogenic process. It is clear from the history of oncology that tumors arise as a result of the acquisition of large numbers of genetic alterations, particularly during the advanced stages of