Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies

Abstract

Anaplastic thyroid cancer (ATC) is a rare malignancy. While external beam radiation therapy has improved locoregional control, the median survival of w 4 months has not changed in more than half a century due to uncontrolled systemic metastases. The objective of this study was to review the literature in order to identify potential new strategies for treating this highly lethal cancer. PubMed searches were the principal source of articles reviewed. The molecular pathogenesis of ATC includes mutations in BRAF, RAS, catenin (cadherin-associated protein), beta 1, PIK3CA, TP53, AXIN1, PTEN, and APC genes, and chromosomal abnormalities are common. Several microarray studies have identified genes and pathways preferentially affected, and dysregulated microRNA profiles differ from differentiated thyroid cancers. Numerous proteins involving transcription factors, signaling pathways, mitosis, proliferation, cell cycle, apoptosis, adhesion, migration, epigenetics, and protein degradation are affected. A variety of agents have been successful in controlling ATC cell growth both in vitro and in nude mice xenografts. While many of these new compounds are in cancer clinical trials, there are few studies being conducted in ATC. With the recent increased knowledge of the many critical genes and proteins affected in ATC, and the extensive array of targeted therapies being developed for cancer patients, there are new opportunities to design clinical trials based upon tumor molecular profiling and preclinical studies of potentially synergistic combinatorial novel therapies.

Anaplastic Transformation of Papillary Thyroid Carcinoma Only Seen in Pleural Metastasis: A Case Report with Review of the Literature

“…There are significant difficulties in distinguishing ATC from other malignant neoplasms at metastatic sites due to partial or complete loss of morphologic and immunohistochemical differentiation, and a high degree of morphological overlap with other anaplastic sarcomatoid malignant neoplasms [16]. Presence of differentiated thyroid carcinoma component or demonstration of the thyroid specific markers, including positive testing for thyroglobulin and TTF-1, supports diagnosis of ATC.…”

An update on molecular biology of thyroid cancers

“…It is known that molecular changes that characterize ATC are: inactivation of the TP53 gene or activation of the PI3K cascade, RAS family members, or BRAF [123,124]. Mouse thyroid follicular cells were used in the study for which inactivation of the TP53 gene was combined with constitutive activation of the PI3K signaling cascade, via deletion of the PTEN tumor suppressor.…”

Sphingosine 1-phosphate and human ether-a′-go-go-related gene potassium channels modulate migration in human anaplastic thyroid cancer cells

“…Due to its high invasive potential, mainly to lungs, brain, and bones, the patient has an average life span of 3-5 months after diagnosis (Nagaiah et al 2011). Currently, there is no effective treatment available (Smallridge et al 2009). Sphingosine 1-phosphate (S1P) is a bioactive lipid regulating many cellular processes, including cell migration and proliferation.…”