Thyroidectomy with neoadjuvant PLX4720 extends survival and decreases tumor burden in an orthotopic mouse model of anaplastic thyroid cancer.

Abstract

BACKGROUND: B-Raf(V600E) is a frequent mutation in anaplastic thyroid cancers and is a novel therapeutic target. We hypothesized that PLX4720 (an inhibitor of B-Raf(V600E)) and thyroidectomy would extend survival and would decrease tumor burden in a mouse model. METHODS: Orthotopic anaplastic thyroid tumors were induced in severe combined immunodeficient mice. Mice were treated with PLX4720 or vehicle after 7 days of tumor growth, and thyroidectomy or sham surgery was performed at day 14. The neck space was re-explored, and tumor volume was measured at day 35. Mice were sacrificed when they lost >25% of their initial weight. RESULTS: All 5 mice that received the vehicle developed cachexia, had invasive tumors (average 61 mm(3))and were sacrificed by day 35. All 6 mice receiving PLX4720 + sham had small tumors (average 1.3 mm(3)) and maintained their weight. Three out of 6 mice receiving PLX4720+thyroidectomy had no evidence of tumor at 35 days; the other 3 mice had small tumors (average 1.4 mm(3)) and showed no signs of metastatic disease. All mice treated with PLX4720 were alive and well-appearing at 50 days. CONCLUSION: Thyroidectomy with neoadjuvant PLX4720 could be an effective therapeutic strategy for early anaplastic thyroid cancers that harbor the B-Raf(V600E) mutation and are refractory to conventional therapeutic modalities.