Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2014) 35 S22.3 | DOI: 10.1530/endoabs.35.S22.3

ECE2014 Symposia Novel therapies for thyroid cancer (3 abstracts)

Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer

J Fagin

Memoria Sloan Kettering Cancer Center, New York, USA.

Oncogenic activation of MAPK in thyroid cells leads to loss of expression of genes required for thyroid hormone biosynthesis, including the sodium iodide transporter (NIS) and thyroid peroxidase (TPO). Tumors with BRAF mutation have lower expression of NIS, explaining in part why BRAF-mutant PTCs are often resistant to RAI therapy. We developed mouse models of thyroid cancer driven by BRAFV600E, and these tumors also lose the ability to concentrate radioiodine, which is restored by treatment with RAF or MEK inhibitors (Chakravarty D et al. J Clin Invest 2012). We conducted a 20 patient study to determine if the MAPK-kinase 1/2 (MEK 1/2) inhibitor selumetinib could reverse RAI-refractoriness in patients with metastatic thyroid cancer. Median age of the 20 evaluable patients was 61 (range 44–77) years and 11 were men. Nine patients had tumours carrying mutations of BRAF and 5 of NRAS. Selumetinib increased 124I incorporation in 12/20 (4/9 BRAF; 5/5 NRAS). Eight of these 12 reached the lesional dosimetry (2000 cGy) threshold to justify RAI therapy, including all 5 NRAS cases. Of the 8 patients treated with RAI, 5 had confirmed partial responses and 3 stable disease; all patients had decreases in serum thyroglobulin (mean percent reduction of 89%). No toxicities grade 3 attributable to selumetinib were observed (Ho A et al. N Engl J Med 2013). These beneficial results were seen although selumetinib does not fully block MAPK signaling in thyroid cancer cells, because they relieve a feedback leading to upregulation of receptor tyrosine kinases, in particular HER3, which confers resistance to therapy (Montero-Conde C et al. Cancer Discovery 2013). New preclinical evidence from our lab now shows that combination therapies that induce a more profound and sustained inhibition of the MAPK transcriptional output in mouse models of Braf-induced thyroid cancer are associated with marked enhancement of expression of thyroid differentation markers, 124-iodine incorporation, and response to 131-iodine therapy, providing a rationale to apply these approaches to patients with high risk thyroid cancer.

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