Molecular pathways and emerging therapeutic strategies in advanced thyroid cancer: from targeted therapy to precision oncology.

The most prevalent endocrine cancer is thyroid cancer. It may act in a very disparate manner; ranging between slow growing, well differentiated tumours to an aggressive anaplastic subtype. Initial treatment with standard therapy, surgery, radioactive iodine, the thyroid-stimulating hormone inhibition and in some cases, chemotherapy or external-beam radiations are effective with the differentiated cancers at the early stages. Nevertheless, there is no choice with tumours, which become unresponsive to iodine, metastasized, or un- differentiated. Recent developments in molecular oncology have elucidated the genetic alterations that contribute to thyroid cancer, in particular, the MAPK and PI3K/AKT/mTOR pathways, and BRAF, RAS, RET, and TERT promoter mutations. The current review summarizes the changing therapeutic environment of thyroid cancer that includes established targeted medicines and novel developments. These are immune checkpoint inhibitors, redifferentiation based on reinstatement of iodine uptake, selective RET and BRAF/MEK, RNA-based therapeutics, CRISPR gene editing, oncolytic virotherapy, peptide receptor radionuclide therapy, alpha-particle radiotherapy, and nanotechnology-based drug delivery systems. A combination regimen involving molecular targeting and immunotherapy or radioactive iodine is also improving the disease in advanced disease. Collectively, the advances are an indication of a transition to the personalized, mechanism-driven treatment strategies that would prolong the survivability of patients with advanced thyroid cancer, conquer resistance, and reduce systemic toxicity.