Copper chelation as targeted therapy in a genetic mouse model of oncogenic BRAF-driven thyroid cancer.

Abstract

e23148 Background: Over half of papillary thyroid cancers (PTC) contain the MAPK pathway activating, oncogenic BRAF V600E mutation. Early clinical trials using inhibitors to this mutant protein or its substrates, the MEK1/2 kinases, prolonged progression-free survival or stabilized disease in patients with advanced PTC. However, the toxicities of these inhibitors are uniquely highlighted in an indolent disease like PTC, which would require patients to endure toxicities long-term. Our goal was to determine if tetrathimoybdate (TM), a well-tolerated copper chelator we have previously shown to inhibit BRAF-mutated melanoma via MEK inhibition, can inhibit BRAF-driven PTC growth. Methods: We assessed TM in comparison to current standard of care (SOC), Lenvatinib and Sorafenib, and mutant BRAF inhibitor, Vemurafenib. Anchorage independent growth assays were used to test the inhibitory effect of these drugs on human BRAF-mutated PTC cell lines. We then confirmed these findings by treating a genetically engineered mouse model (GEMM) of aggressive BRAF-driven PTC. Results: TM inhibited 57.5% of colony growth in vitro, which was not significantly different from the 42.4% and 32.2% inhibition by Sorafenib and Lenvatinib, respectively. TM inhibition was less effective than the 70.3% inhibition by Vemurafenib ( p =0.04). We confirmed these results in vivo, where mice on the TM arm, on average, were observed to have 14.8% of their thyroid glands occupied by tumor, a statistically significant reduction from the mice in the control arm, whose tumor load averaged 23.6% ( p= 0.008). This 37.4% reduction in tumor burden was not statistically different from the 35.2% reduction measured in the Vemurafenib arm, where mice on average had 15.3% of their thyroid glands replaced by tumor. Conclusions: The copper chelator, TM, was as effective as the SOCs, Lenvatinib and Sorafenib, at inhibiting the growth of human PTC in vitro. Although TM was slightly less effective than Vemurafenib in vitro, TM was as effective as Vemurafenib at reducing tumor load in a GEMM of BRAF-driven PTC. Success of TTM in these PTC models may next inform a Phase I trial assessing TM in patients with advanced PTC.