Abstract 608: Quinacrine and sorafenib as potential combination for anaplastic thyroid carcinoma.

Abstract

Abstract Anaplastic thyroid cancer (ATC) comprises ∼2% of all thyroid cancers and its median survival rate remains poor. ATC is frequently resistant to conventional therapy and therefore it is essential to expand the number of treatment options for ATC. Proto-oncogenes RET, RAS and BRAF are some of the best targets described in thyroid cancer. Sorafenib is a small molecule multi-kinase inhibitor that inhibits RAF, MEK and ERK kinases among other targets and is therefore being evaluated in several phase II/III clinical trials in thyroid cancer. Quinacrine, a potent small molecule inhibitor of NFKB signaling, is currently being evaluated in phase II clinical trials. We have previously shown the effectiveness of quinacrine in combination with cytotoxic drugs in hepatocellular and colon carcinoma cells acts by inhibiting NFKB, Mcl-1, and angiogenesis in tumor cell lines that are deficient in p53. Here, we evaluate the efficacy of quinacrine in combination with sorafenib on a panel of human ATC cells. Quinacrine as a single agent effectively inhibits growth and promote apoptosis of ATC cells in vitro in a dose-dependent manner as assessed by CellTiter-Glo and sub-G1 analysis respectively. Combinatorial dose-response modulation of quinacrine with sorafenib suggests a synergistic drug-drug interaction with respect to growth stasis of ATC cells in vitro, as defined by Chou-Talalay. Western blot analysis suggest that the anti-apoptotic Bcl-2 family member Mcl-1, over-expressed in a number of solid tumors, is efficiently down-regulated in the ATC cell line 8505C by the combination of quinacrine and sorafenib. We also observe that the active form of transcription factor Stat3 is down-regulated by both quinacrine and sorafenib. In contrast to chloroquine that inhibits autophagy, our previous results have not shown that quinacrine's anti-tumor efficacy involves alterations in autophagy. Furthermore, sorafenib and quinacrine significantly improve survival in a mouse thyroid orthotopic in vivo xenograft model of ATC. We are currently exploring the detailed molecular mechanism of the quinacrine and sorafenib drug synergy and associated anti-tumor activity in vitro and in vivo. In addition, we are exploring the possibility of performing in vivo assays of the therapy combination with clinical samples. Our findings suggest that quinacrine in combination with sorafenib may be a novel and potentially cost effective therapeutic strategy for the treatment ATC. Citation Format: Junaid Abdulghani, Jean-Nicolas Gallant, Tiffany Whitcomb, David Dicker, David Goldenberg, Charles D. Smith, Niklas Finnberg, Wafik S. El-Deiry. Quinacrine and sorafenib as potential combination for anaplastic thyroid carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 608. doi:10.1158/1538-7445.AM2013-608