Memorial Sloan Kettering stands poised to lead a multicenter international phase III registration trial of a drug that inhibits the overactive MAP kinase pathway following a groundbreaking New England Journal of Medicine study in which our researchers for the first time demonstrated that thyroid cancers refractory to radioiodine can be made to take up therapeutic iodine.
Selumetinib is a small molecule that blocks MAP kinase (MEK), the enzyme just downstream of BRAF. In the pilot study from 2013, eight of 20 patients showed enough increase in iodine uptake in their tumors after four weeks on selumetinib to warrant a therapeutic dose of radioiodine. All five patients with RAS mutations fell into this category, along with one of the nine subjects with a BRAF mutation.
At six months, five of these eight patients experienced a 30 percent or more decrease in tumor volume and the other three showed stable disease. On average, these individuals had an 80 percent drop in thyrotropin-suppressed serum thyroglobulin levels after six months.
The research was led by physician-scientist James Fagin, Chief of the Endocrinology Service and immediate past president of the American Thyroid Association. The article’s lead author was medical oncologist Alan Ho.
Groundbreaking Work in Precision Medicine
The foundation for these critical findings was the 2003 discovery by Dr. Fagin’s lab that an activating mutation in the BRAF gene is the most common genetic change in adult papillary thyroid cancer. BRAF is a signaling component of the MAP kinase pathway, a protein cascade through which cells respond to external growth factors. The mutated form of BRAF causes this growth pathway to be constantly activated. In contrast, follicular thyroid cancers frequently harbor a mutation in RAS, the enzyme just upstream of BRAF that has the effect of turning on the same growth pathway.
A result of this aberrant signaling is a dramatic decrease in the expression of the sodium-iodide symporter, resulting in thyroid tumors with these mutations failing to readily take up iodine. This poses a treatment dilemma because radioactive iodine can no longer be used to destroy metastatic disease.
The results of this pilot study provide proof of principle that MEK inhibitors can shut down the runaway signaling and restore the tumor’s ability to absorb iodine.
Dr. Fagin’s lab continues to pursue multiple related topics in thyroid cancer, including assessment of the genetics that underlie poorly differentiated and anaplastic thyroid cancers and exploration of the mechanisms that allow thyroid cancers to be resistant to drugs that target BRAF.Back to top
NIH Award Brightens Prospect of New Findings for Thyroid Cancer Patients
In October 2014, Dr. Fagin and his co-investigators received a prestigious National Institutes of Health Specialized Programs of Research Excellence (SPORE) grant of roughly $10 million over five years to support research into thyroid disease pathogenesis with the goal of improving outcomes for patients at all stages of disease.
As part of this award, the team will take advantage of MSK’s strong training environment in clinical and scientific programs to identify and promote the research and training of young investigators focused on translational thyroid cancer research.Back to top