Abstract 2527: The drug combination sorafenib and quinacrine targets the expression of Mcl-1 - an anti-apoptotic protein and candidate prognostic factor in Anaplastic Thyroid Cancer (ATC)

Abstract

Abstract Anaplastic thyroid cancer (ATC) is a rare, highly aggressive form of thyroid cancer that frequently is resistant to conventional therapy and therefore requires the development of efficacious novel therapy. Sorafenib, a multi-kinase inhibitor that inhibits the RAF, MEK and ERK kinases, was recently approved by the FDA for late stage metastatic differentiated thyroid cancer but appears to have limited activity in ATC by itself. Sorafenib-based drug combinations with complimentary drug targets are being pursued and evaluated preclinically. However, sorafenib generates a significant number of adverse events in thyroid cancer patients and drug combinations including sorafenib needs to be carefully tailored with respect to toxicity and efficacy. We have previously shown that quinacrine, a potent small molecule inhibitor of NFKB signaling, combine favorably with several cytotoxic drugs to target hepatocellular and colorectal cancer cells. Quinacrine is an inexpensive drug, has a well established safety profile in human subjects and is being evaluated in cancer clinical trials. Subsequently, we decided to evaluate the efficacy of the drug combination of quinacrine and sorafenib in ATC. Our combinatorial dose-response modulation of quinacrine with sorafenib suggests a synergistic drug-drug interaction with respect to growth stasis in a panel of ATC cells in vitro, as defined by Chou-Talalay. Furthermore, in vivo the drug combination of sorafenib and quinacrine significantly improved survival compared to vehicle control and the current first line chemotherapeutic doxorubicin in a mouse thyroid orthotopic xenograft model of ATC. Dose-escalation toxicity studies in mice suggest that the drug combination was well tolerated and did not trigger synergistic toxicities compared to either drug alone. Significantly less gastrointestinal injury, the most commonly observed toxicity in our study, was present following treatment with the drug combination of sorafenib and quinacrine compared to treatment with doxorubicin alone. Western blot analysis suggests that the anti-apoptotic Bcl-2 family member Mcl-1 is a target for the drug combination. Indeed, immunohistochemical (IHC) analysis of resected ATC and non-neoplastic thyroid tissues from patients confirmed overexpression of Mcl-1 in ATC indicating target availability. Interestingly, multi-regression analysis of our patient IHC data suggest that high Mcl-1 expression together with tumor size prognosticated poor survival in ATC patients suggesting that Mcl-1 overexpression was linked to a more aggressive tumor behavior. In conclusion, our findings suggest that quinacrine in combination with sorafenib may be a novel and potentially cost effective therapeutic strategy to target Mcl-1, whose expression potentially may be linked to the disease progression of ATC. Citation Format: Junaid Abdulghani, Jean-Nicholas Gallant, Prashanth Gokare, Timothy Cooper, Tiffany Whitcomb, Jiangang Liao, Jing Liu, David Goldenberg, Niklas K. Finnberg, Wafik S. El-Deiry. The drug combination sorafenib and quinacrine targets the expression of Mcl-1 - an anti-apoptotic protein and candidate prognostic factor in Anaplastic Thyroid Cancer (ATC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2527. doi:10.1158/1538-7445.AM2015-2527