title: Personalized therapy in patients with anaplastic thyroid cancer: targeting genetic and epigenetic alterations.
abstract: BACKGROUND
  Anaplastic thyroid cancer (ATC) is the most lethal of all thyroid cancers and one of the most aggressive human carcinomas. In the search for effective treatment options, research toward targeted, personalized therapies is proving to be a path with great potential. As we gain a deeper understanding of the genetic (eg, BRAF(V600E), PIK3CA, TP53, hTERT mutations, etc) and epigenetic (eg, histone methylation, histone de-acetylation, microRNA regulatory circuits, etc) alterations driving ATC, we are able to find targets when developing novel therapies to improve the lives of patients. Beyond development, we can look into the effectiveness of already approved targeted therapies (eg, anti-BRAF(V600E) selective inhibitors, tyrosine kinase inhibitors, histone deacetylase inhibitors, inhibitors of DNA methylation, etc) to potentially test in ATC after learning the molecular mechanisms that aid in tumor progression.
  
  
  METHODS
  We performed a literature analysis in Medline through the PubMed web site for studies published between 2003 and 2014 using the following main keywords: anaplastic thyroid cancer, genetic and epigenetic alterations.
  
  
  OBJECTIVE
  Here, we outlined the common pathways that are altered in ATC, including the BRAF(V600E)/ERK1/2-MEK1/2 and PI3K-AKT pathways. We then examined the current research looking into personalized, potential targeted therapies in ATC, mentioning those that have been tentatively advanced into clinical trials and those with the potential to reach that stage. We also reviewed side effects of the current and potential targeted therapies used in patients with advanced thyroid cancer.
  
  
  CONCLUSIONS
  DNA and RNA next-generation sequencing analysis will be fundamental to unraveling a precise medicine and therapy in patients with ATC. Indeed, given the deep biological heterogeneity/complexity and high histological grade of this malignancy and its tumor microenvironment, personalized therapeutic approaches possibly based on the use of combinatorial targeted therapy will provide a rational approach when finding the optimal way to improve treatments for patients with ATC.
authors.affiliation: Laboratory of Human Thyroid Cancers Preclinical and Translational Research, Division of Cancer Biology and Angiogenesis, Department of Pathology, Center for Vascular Biology Research, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215.
authors.forename: Neal
authors.initials: N
authors.lastname: Smith
authors.forename: Carmelo
authors.initials: C
authors.lastname: Nucera
mesh_terms: D044127:Epigenesis, Genetic; D006801:Humans; D057285:Precision Medicine; D015398:Signal Transduction / Q000235:genetics*; D065646:Thyroid Carcinoma, Anaplastic / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*