Abstract A127: A novel class of compounds that selectively target (ER +ve) breast cancer cells.

Abstract

Abstract Estrogens play an important role in breast cancer development, with approximately 60% of premenopausal and 75% of postmenopausal breast cancer patients having estrogen-dependent carcinomas. In recent decades endocrine therapy has emerged for the treatment of estrogen receptor (ER) positive breast cancer, including aromatase inhibitors (anastrozole) and estrogen receptor antagonists (tamoxifen). However, drug resistance is often induced by these therapies, tumor selectivity is sometimes poor with non-tumor populations being affected, and target selectivity is also a problem with “off-target-effects” culminating in adverse toxicities and/or limited efficacy. For the past ten years collaboration between the Calvary Mater Newcastle Hospital and the University of Newcastle (Australia) has seen the development of many small molecule drugs for the treatment of malignancy. Our recent findings have discovered a family of 2-phenylacrylonitriles showing growth inhibition against a panel of human cancer derived cell lines. Focused library approaches facilitated the identification of a simple pharmacophore, comprising two terminal aromatic moieties linked via a conjugated cyano moiety. Multiple libraries led to the discovery of two key compounds, MT-CN-07 and MT-CN-18. Both exhibit broad spectrum growth inhibition with GI50 values of 3.2–46μM and 3.1–69μM, respectively, in a panel of nine human cancer cell lines derived from colon, ovarian, lung, skin, prostate and pancreatic carcinomas, neuroblastoma and glioblastoma1. An initial screen in one breast cancer ER+ve cell line (MCF-7) suggested that these compounds may selectively target estrogen dependent breast cancer cells. Indeed recent studies have shown that MT-CN-07 and MT-CN-18 are up to 645 fold more potent at inhibiting the growth of ER+ve breast cancer cells (ZR-75–1, T47D, MCF-7) with GI50 values of 0.08–0.6μM, and 0.107–2.25μM, respectively, when compared with the nine cell lines derived from other tumor types. Moreover, these compounds are up to 450 fold more potent in ER+ve breast cancer cell lines when compared with the estrogen independent cell line MDA-MB-231 (ER-ve, GI50 = 36μM and 26μM, respectively) and the non-tumorigenic breast epithelial cell line MCF10A (GI50 = 36μM and 37μM, respectively). Screening of these compounds in the drug resistant, etoposide-selected breast cancer cell line, MCF7/VP, which has amplification and over-expression of the ABCC1 gene, showed they were not substrates for this drug resistant mechanism. The ability to specifically target estrogen dependent tumors, while having little or no effect on normal breast cells, or other tumor types is a unique finding. Thus we have identified a novel group of molecules that could be exploited for the treatment of estrogen sensitive breast cancer. Reference: 1. Tarleton M, Gilbert J, Robertson MJ, McCluskey A, Sakoff JA. (2011) Library synthesis and cytotoxicity of a family of 2-phenylacrylonitriles and discovery of an estrogen dependent breast cancer lead compound. Med Chem Comm. 2, 31–37 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A127.