title: The discovery and development of sorafenib for the treatment of thyroid cancer.
abstract: BACKGROUND
  Although the prognosis for most differentiated thyroid cancers (DTCs) remains excellent, recurrence and insensitivity to radioactive iodine (RAI) lead to therapeutic challenges and poorer outcomes. In defining the pathogenesis of DTC, multiple genetic alterations have been identified in key pathways focused around receptor tyrosine kinases (RTKs) and the MAPK cascade. Sorafenib was specifically developed to target rapidly accelerated fibrosarcoma (RAF) kinase in the MAPK pathway. It has been shown, however, to have potent inhibition of several key RTKs, RAF kinase and the V600E BRAF mutation, gaining FDA approval in November 2013 for advanced RAI-refractory DTC.
  
  
  METHODS
  The authors provide a review of the targeted RAF kinase discovery strategy as well as the preclinical and clinical development of sorafenib, leading to FDA approval of DTC. The authors also provide some insight into the clinical use of sorafenib and look at important considerations for treatment.
  
  
  CONCLUSIONS
  Sorafenib significantly improves progression-free survival in metastatic DTC patients who are RAI-refractory. However, the overall survival benefit is still unproven and requires additional follow up. Despite its cost and significant side-effect profile, which results in dose reductions in the majority of DTC patients, sorafenib should be considered for the treatment of RAI-refractory advanced DTC patients following evaluation of their individual risk-benefit stratification.
authors: University of Michigan Health System, Department of Surgery , 1500 E Medical Center Dr SPC 5332, Taubman Center Floor 2 Reception F, Ann Arbor, MI 48109 , USA.
authors: Peter T
authors: PT
authors: White
authors: Mark S
authors: MS
authors: Cohen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D018572:Disease-Free Survival; D017277:Drug Approval; D015195:Drug Design; D006801:Humans; D058990:Molecular Targeted Therapy; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000077157:Sorafenib; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib
keywords: differentiated thyroid cancer; sorafenib; thyroid cancer; thyroid cancer treatment; tyrosine kinase inhibitor