Anaplastic thyroid cancer (ATC) is the most aggressive type of thyroid cancer, and there is an urgent need to develop model systems so that new drugs can be tested. Despite our efforts to maximize the combined treatment approaches integrating surgery, radiation and chemotherapy, most patients diagnosed with ATC experience disease progression and succumb to this terrible illness. The rarity of ATC has limited our ability to systematically test new drugs. For this reason model organisms that recapitulate the key genetic aspects of ATC are highly desirable. We have made little to no headway with standard therapeutic tools. A more sophisticated targeted approach will likely be required to improve treatment options and offer hope for improving survival.
Newly elected ITOG member Dr. David McFadden, from the Massachusetts General Hospital Center for Endocrine Tumors and the David H. Koch Institute for Integrative Cancer Research at MIT, along with colleagues, generated a genetically-engineered mouse that superimposes loss of the tumor suppressor gene, TP53, on a BRAF(V600E) mutation in mouse thyroid tissue. This work was published online Monday, April 7th, 2014, in the Proceedings of the National Academy of Sciences. This model recapitulated both the molecular biology and the natural history of ATC in humans remarkably well. BRAF(V600E) mutations are considered to be the most common initiating genetic alteration in thyroid cancer, whereas TP53 mutations seem to play the greatest role late in progression of only the most aggressive thyroid tumors. In Dr. McFadden’s ATC mouse model, induction of mutant BRAF led to thyroid tumors with papillary histology and slow growth limited to the thyroid gland. When crossed with mutant TP53 alleles, ATC rapidly emerged out of the papillary thyroid cancers and exhibited explosive growth.
The greatest promise for this new ATC mouse model is, perhaps, its utility in studying new treatment approaches for this rare and devastating disease. To this end, McFadden and colleagues found that treatment with single agent BRAF inhibition had very little activity against the murine ATCs, but when a downstream MEK inhibitor was added to the BRAF inhibitor, the MAPK pathway was shut down more completely and ATC growth was inhibited more effectively. These data may be readily applicable to ATCs in humans that harbor mutant BRAF V600E, and will hopefully be translated directly to clinical trial development.
For more information about Dr. McFadden's ATC mouse model see this link: http://www.newswise.com/articles/mit-biologists-from-the-koch-institute-...
For subscribers with access to PNAS online the full text of the article is here: http://www.pnas.org/content/early/2014/04/04/1404357111