Novel targeted therapies and immunotherapy for advanced thyroid cancers

Abstract

Thyroid cancer is a frequently encountered endocrine malignancy. Despite the favorable prognosis of this disease, 15–20% of differentiated thyroid cancer (DTC) cases and most anaplastic types, remain resistant to standard treatment options, including radioactive iodine (RAI). In addition, around 30% of medullary thyroid cancer (MTC) cases show resistance after surgery. The evolving understanding of disease-specific molecular therapeutic targets has led to the approval of two targeted therapies (Sorafenib and Lenvatinib) for RAI refractory DTC and another two drugs (Vandetanib and Cabozantinib) for MTC. These advanced therapies exert their effects by blocking the MAPK pathway, which has been widely correlated to different types of thyroid cancers. While these drugs remain reserved for thyroid cancer patients who failed all treatment options, their ability to improve patients’ overall survival remain hindered by their low efficacy and other molecular factors. Among these factors is the tumor’s ability to activate parallel proliferative signaling pathways other than the cascades blocked by these drugs, along with overexpression of some tyrosine kinase receptors (TKR). These facts urge the search for novel different treatment strategies for advanced thyroid cases beyond these drugs. Furthermore, the growing knowledge of the dynamic immune system interaction with tumor microenvironment has revolutionized the cancer immune therapy field. In this review, we aim to discuss the molecular escape mechanisms of thyroid tumors from these drugs. We also highlight novel therapeutic options targeting other pathways than MAPK, including PI3K pathway, ALK translocations and HER2/3 receptors and their clinical impact. We also aim to discuss the usage of targeted therapy in restoring thyroid tumor sensitivity to RAI, and finally turn to extensively discuss the role of immunotherapy as a potential alternative treatment option for advanced thyroid diseases.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0786-0) contains supplementary material, which is available to authorized users.

Medullary thyroid carcinoma beyond surgery: advances, challenges, and perspectives

“…In the last few years, immunotherapy has transitioned from a promising to a well-established option as an oncological treatment for several types of malignancies, acting as an immune checkpoint inhibitor (Emens et al 2017). Preclinical studies on MTC have revealed potential new treatments through the use of immunotherapy (Naoum et al 2018). Several ongoing trials are investigating this type of therapy, including a phase II trial studying a therapy directed toward cells presenting CEA (GI-6207), a therapy focused on programmed death ligand 1 (PDL1) with the use of pembrolizumab (Arasanz et al 2017).…”

Clonal evolution analysis of paired anaplastic and well‐differentiated thyroid carcinomas reveals shared common ancestor

“…The dismal prognosis of this rare thyroid malignancy has led to substantial efforts to find the genetic drivers in hopes of developing targeted therapy to improve survival . Previous studies have identified a variety of potential genetic driver events in many ATCs, but a clear understanding of the molecular pathogenesis remains far from complete.…”

Combinatorial Therapies in Thyroid Cancer: An Overview of Preclinical and Clinical Progresses

“…In the context of cancer, MAPK and PI3K signaling pathways are parts of the most successfully studied pathways [39]. These pathways include various gene alterations (mutation, amplification, and deletion) that may contribute to the carcinogenesis and that this may be targeted for therapies.…”

“…PTEN is known to antagonize the PI3K/AKT pathway and its loss stimulates this pathway. Around 12% of ATC exhibit mutated or deleted PTEN genes leading to an overactivation of the PI3K/AKT pathway and a more aggressive tumor [39].…”

“…Furthermore, Sherman et al evaluated the potential efficacy of the association of the multikinase inhibitor sorafenib and the temsirolimus (a mTOR inhibitor) in patients with radioactive iodine refractory thyroid cancer. Sorafenib alone is already approved for treatment by the Food and Drug Administration (FDA) in the case of advanced renal carcinoma (2005), unresectable hepatocellular carcinoma (2007) and locally recurrent or metastatic, progressive differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment (2013) [39]. The inhibitory effects of sorafenib were evaluated in the international multicentric phase III DECISION study.…”