1. Novel selective estrogen receptors degraders regress tumors in pre-clinical models of endocrine-resistant breast cancer.
- Author
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Hager, J. H., Darimont, B., Joseph, J., Govek, S., Grillot, K., Aparicio, A., Bischoff, E., Kahraman, M., Kaufman, J., Lai, A., Lee, K.-J., Lu, N., Nagasawa, J., Prudente, R., Qian, J., Sensintaffar, J., Shao, G., Heyman, R., Rix, P., and Smith, N. D.
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ESTROGEN receptors , *BREAST cancer research , *HORMONE synthesis , *TUMORS , *CELL lines - Abstract
80% of all breast cancers express the estrogen receptor alpha (ERκ) and thus are treated with anti-hormonal therapies that directly block ER function (e.g. Tamoxifen) or hormone synthesis (Aromatase Inhibitors). While these therapies are initially effective, acquired resistance invariably emerges. Importantly, the majority of these tumors continue to depend on ERκ for growth and survival. The emerging evidence that ERa can signal in both a ligand-dependent and ligand-independent manner supports the development of agents that are not only competitive ERκ antagonists but also reduce steady state levels of the receptor and thus limit both modes of signaling. We have identified novel, non-steroidal ERa antagonists that induce degradation of ERa in breast cancer cell lines at picomolar concentrations resulting in significant reduction in steady state ERa protein levels. Using peptide-based conformational profiling, we show that these Selective Estrogen Receptor Degraders (SERDs) induce estrogen receptor conformations that are distinct from both fulvestrant and tamoxifen indicating a unique mechanism of action. This unique biological profile coupled with good oral pharmacokinetics produces tumor regressions in both tamoxifen-sensitive and -resistant models of breast cancer in vivo. Recent pre-clinical and clinical data indicate that PI3K pathway signaling can contribute to the endocrine resistant state. In a preclinical model of tamoxifen resistant breast cancer in which SERD monotherapy only produces tumor growth inhibition, SERD therapy in combination with torc1/2 inhibition results in frank tumor regressions. These orally bioavailable SERDs hold promise as a next generation therapy for the treatment of ER+ breast cancer as monotherapy, as well as in combination with agents that target other pathways involved in both intrinsic and acquired endocrine resistance. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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