New drugs for medullary thyroid cancer: new promises?

Abstract

Medullary thyroid cancer (MTC) is a rare tumor arising from the calcitonin-producing parafollicular C cells of the thyroid gland, occurring either sporadically or alternatively in a hereditary form based on germline RET mutations in approximately one-third of cases. Historically, patients with advanced, metastasized MTC have had a poor prognosis, partly due to limited response to conventional chemotherapy and radiation therapy. In the past decade, however, considerable progress has been made in identifying key genetic alterations and dysregulated signaling pathways paving the way for the evaluation of a series of multitargeted kinase inhibitors that have started to meaningfully impact clinical practice. Two drugs, vandetanib and cabozantinib, are now approved in the US and EU for use in advanced, progressive MTC, with additional targeted agents also showing promise or awaiting results from clinical trials. However, the potential for toxicities with significant reduction in quality of life and lack of curative outcomes has to be carefully weighed against potential for benefit. Despite significant PFS prolongation observed in randomized clinical trials, most patients even with metastatic disease enjoy indolent courses with slow progression observed over years, wherein watchful waiting is still the preferred strategy. As advanced, progressive MTC is a rare and complex disease, a multidisciplinary approach centered in specialized centers providing interdisciplinary expertise in the individualization of available therapeutic options is preferred. In this review, we summarize current concepts of the molecular pathogenesis of advanced MTC and discuss results from clinical trials of targeted agents and also cytotoxic chemotherapy in the context of clinical implications and future perspectives.

Selective Ablation of Tumor Suppressors in Parafollicular C Cells Elicits Medullary Thyroid Carcinoma

“…This underscores the urgent issue of identifying new drug targets for treating medullary thyroid carcinomas. Because RET mutations (denoted RET(ϩ)) have been well documented in hereditary medullary thyroid carcinoma and in a significant fraction of sporadic medullary thyroid carcinoma, inhibitors of RET are proven for clinical use in treating these patients (37,38). Conceivably, tumor cells would eventually develop resistance to RET inhibitors as has been observed in other types of cancers that are initially sensitive to receptor tyrosine kinase inhibitors (39).…”

Thyroid Cancer: Risk-Stratified Management and Individualized Therapy

“…Selumetinib, a MEK1/2 inhibitor was found to reverse refractoriness to RAI in patients with metastatic DTC (104). Details of clinical trials in thyroid cancer are summarized in Table 1 and can be found elsewhere (105,106). A limitation of targeted therapy is the development of an escape mechanism.…”

Long non-coding RNAs in anti-cancer drug resistance

“…With the advent of various anticancer drugs, cytotoxic and molecularly targeted compounds have become the first-line standard treatment regimens for most cancer patients when surgery is not an appropriate option [1, 2]. In 2004, it was first reported that a mutation in the epidermal growth factor receptor (EGFR) conferred a clinical response to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC).…”