Abstract B42: The sigma-2 receptor as a target for therapeutic drug delivery in triple negative breast cancer

Abstract

Abstract Introduction: Triple Negative Breast Cancer (TNBC) is an aggressive form of breast cancer and typically results in poor patient prognosis. While other breast cancer subtypes benefit from targeted therapies, TNBC currently has no approved agents. The sigma-2 receptor has been validated as a proliferation marker and also a site for therapeutic drug delivery in ovarian and pancreatic cancer. In this study we evaluated the sigma-2 receptor as a target for therapeutic drug delivery in TNBC using a sigma-2 targeting vehicle conjugated to a small molecule activator of caspases(SMAC) mimetic, SW-IV-134. Methods: Triple negative breast cancer cell lines; MDA-MB-231, HCC1937 and HCC1806 were tested for sensitivity to sigma-2 targeted compound SW-IV-134 vs. Taxol or the deconstructed conjugate subparts. 2 hr and 48 hr treatments we assessed to determine whether there was a significant in vitro targeting effect. Sigma-2 expression was quantified through radioligand saturation studies using cell homogenate tissue and the Ki value of SW-IV-134 for the sigma-2 receptor was calculated through competitive inhibition studies. Caspase 3/7 activation was assessed after 2 or 48 hr treatments. Results: SW-IV-134 was the most potent treatment in MDA-MB-231 and HCC1937, while no difference from taxol was found in HCC1806. Sigma-2 receptor expression was found to be the highest in the MDA-MB-231 and no difference was found in HCC1937 and HCC1806. The Ki of SW-IV-134 for the sigma-2 receptor was 23 nM and is consistent with previously reported values. Caspase 3/7 activation was detected in all cell lines following treatment at 2 and 48 hr. The greatest caspase 3/7 activation was observed in the MDA-MB-231 cell line. Conclusion: The sigma-2 receptor is expressed at different levels on the three TNBC cell lines and the receptor expression corresponds to therapeutic efficacy. SW-IV-134 was the most potent therapeutic tested in two of the three cell lines with no difference between taxol observed in HCC1806. This study shows the sigma-2 receptor is a target that can be exploited for therapeutic drug delivery in three TNBC cell lines and may provide a platform for future targeted therapy development for TNBC. Citation Format: Mehran Makvandi, Estifanos D. Tilahun, Brian P. Lieberman, Kuiying Xu, Chenbo Zeng, Catherine Hou, Robert H. Mach. The sigma-2 receptor as a target for therapeutic drug delivery in triple negative breast cancer. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B42.