Abstract A91: Developing novel treatment strategies for triple-negative breast cancer metastasis

Abstract

Abstract Despite the significant advances in breast cancer biology, there has been limited progress in the treatment of advanced breast cancer, with little change in the overall survival for women with metastatic breast cancer over the last several decades. There were approximately 180,000 new cases of breast cancer diagnosed in the United States in 2007. About 15% of these, accounting for 25,000 to 30,000 cases each year, are “triple-negative breast cancer” (TNBC) in that the tumors do not express the estrogen receptor (ER), progesterone receptor (PR), or HER-2/neu. Unlike therapies targeted against steroid hormone receptors or HER2, there is no Food and Drug Administration (FDA) approved targeted drugs for the treatment of TNBC, and hence these cancers are associated with the worst prognosis with patients ultimately succumbing to metastatic disease. Systemic therapies are effective initially in controlling and reversing tumor growth; however, residual cancers will invariably re-grow despite this initial response causing recurrence or metastasis at distant sites. The identification of new therapeutic targets against TNBC is crucial to improving the outcome of this subtype. Our goal is to eliminate TNBC metastasis by developing novel therapies capable of attacking and destroying the “lethal seeds” driving these cancers and metastases, the “tumor initiating cells” (TICs) or “cancer stem cells” (CSCs). Hypothesis: Targeting cancer stem cells will eliminate metastasis, ultimately improving survival in TNBC. Data from paired clinical human breast cancer biopsies showed that standard therapy every three weeks kills dividing daughter cells but not tumor-initiating cells (TICs), so that tumor tissue obtained after therapy is enriched for “tumor-initiating” or “cancer stem” cells. Using patient-derived tumorgraft models, we further discovered that despite complete eradication of primary TNBC tumors by multiple cycles of standard chemotherapy, metastases in distant sites ultimately developed, causing death. We analyzed the gene expression of CSC isolated from patient biopsies to identify therapeutic targets regulating CSCs. Based on the signaling pathways identified through this microarray analysis, we treated mice with small molecule inhibitors of STAT3 or the Notch signaling pathway and showed remarkable reduction of CSCs in primary tumors. We expect that the addition of CSC-targeted therapy to standard chemotherapy will eliminate metastasis. Single agent targeted therapy may only reduce metastatic burden, suggesting a cocktail of targeted-therapies will be required to eradicate metastasis, in which case, we would combine multiple therapies that target CSCs. Citation Format: Melissa D. Landis, Lacey A. Burey, Jenny C. Chang. Developing novel treatment strategies for triple-negative breast cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A91.