Emerging Therapies in Sight for the Fight against Dedifferentiated Thyroid Cancer

Abstract

In the preface of the book he edited (1), and to which Nick Sarlis and I had the privilege of contributing a chapter that is pertinent to this editorial, the late Nadir Farid wrote, “Given the relative success we have in its [thyroid cancer] treatment, there is a need to capitalize on it by better understanding the factors that underpin this malignancy, and exploring better strategies for diagnosis, treatment, and follow-up. To do so, we must take full advantage of the revolution in modern biology.” He then alluded to the major advance in therapeutics constituted by the availability of “drugs that might influence the course of poorlydifferentiated thyroidandanaplastic thyroidcancer.” In2006, theAmericanThyroidAssociation (ATA) issuedthe revision of the 1996 guidelines for management of thyroid nodules and differentiated thyroid cancer (DTC), which in November2009wereupdatedagain (2).The2006and2009 ATA guidelines both have a section entitled “What are the directions for future research?” The first heading of this section is entitled “Novel therapies and clinical trials,” and it takes intoaccountthe“minorityofpatients[who]experience progressive, life-threatening growth and metastatic spread of the disease.” The novel therapies were grouped under five categories: inhibitors of oncogenic signaling pathways, modulators of growth or apoptosis, angiogenesis inhibitors, immunomodulators, and gene therapy. As Dr. Leonard Wartofsky, the present JCEM Editor-in-Chief, pointed out in one of the accompanying editorials (3), “Given the flurry of clinical trials with new therapeutic agents that might target thyroid cancer, a significantly expanded section on promising new agents may have been expected. It appears that this will have to wait for the next revision.” Thyroid cancer (TC) is becoming one of the most common cancers in Western countries. More than 90% of TCs are well-differentiated malignancies arising from follicular cells (DTC), which include papillary TC (PTC) and follicular cancer. DTCs are usually curable or controllable by the combination of surgery, radioiodine ablation, and TSH-suppressive therapy; however, approximately 30% of patients have recurrent disease (2). Cell dedifferentiation is usually accompanied by more aggressive growth, metastatic spread, and inability to trap iodide, making the tumor resistant to radioiodine ablation and poorly responsive to conventional chemotherapy and external radiotherapy (4). The reported 10-yr survival rates in dedifferentiated TC (DeTC) patients range from 49 to 68% for locoregional recurrences and from 25 to 42% for distant metastases (4). Therefore, advanced DeTCs represent a therapeutic challenge and are considered a critical area of research. Molecular abnormalities have been detected in PTC (1). In adult sporadic PTC, RET/PTC rearrangements are found in 30–40% of cases, RAS mutations in about 10%, and BRAF mutations in around 40% of cases, with no overlapbetweenthesemutations (5).BRAFmutationshave been associated with less differentiated, more aggressive PTC (1, 5). Overexpression of tyrosine kinase (TK) receptors, and often of their cognate ligands, has been noted in TC cells, including receptors for epidermal growth factor and vascular endothelial growth factor (VEGF). Activated oncogenes are highly attractive targets for the development of new specific anticancer agents, which are therefore supposed to be delivered to patients having a cancer that harbors the cancer-causative activated onco-