Abstract 1193: Treatment of breast cancer xenografts with paclitaxel enriches for cancer stem cells that can be targeted by a ROR1-specific antibody

Although initially responsive to hormone therapy and chemotherapy, many patients with metastatic breast cancer develop resistant and potentially fatal disease. One of the mechanisms of resistance is the emergence of post-treatment survival of a small number of breast cancer stem cells (CSC), which are relatively resistant to chemotherapy, have self-renewal capacity, and can repopulate the tumor and spread to distal sites. New therapies are required to eliminate breast CSC that could be used alone or in combination with standard therapy to mitigate the risk of developing relapsed disease. In this study, treatment of immune-deficient mice bearing breast-cancer patient-derived xenografts (PDX) with paclitaxel reduced tumor volumes, but enhanced the proportion of tumor cells that expressed ROR1, an RTK-like orphan receptor that is ordinarily expressed during embryogenesis. We found that breast cancer tumors with high levels of ROR1 expression were enriched for stem-cell gene-expression signatures. Moreover, cells isolated from breast cancer PDX that were positive for CSC markers such as aldehyde dehydrogenase 1 (ALDH1) were enriched for ROR1 expression, and ROR1+-cells isolated from breast cancer PDX had a greater capacity to form spheroids in vitro or re-engraft immune-deficient mice, than did ROR1-negative (ROR1Neg) cells isolated from the same tumor population. Treatment of breast cancer cells with a humanized anti-ROR1 mAb, UC-961, suppressed expression of the polycomb-ring-finger oncogene Bmi-1, and genes encoding proteins implicated in the epithelial-mesenchymal transition. UC-961 also impaired the capacity of breast-cancer cells to form spheroids or to re-engraft immune-deficient mice. Finally, combined therapy with UC-961 and paclitaxel appeared more effective in reducing re-engraftment potential than either agent alone (Table1). Collectively, this study implies that patients with advanced breast cancer may benefit from anti-CSC therapy, either alone or in combination with conventional anti-cancer drugs. Citation Format: Suping Zhang, Grace Liu, Sam H. Lai, Han Zhang, Emanuela M. Ghia, Bing Cui, Rongrong Wu, George Widhopf, Jian Yu, Richard Schwab, Karen Messer, Barbara Parker, Thomas J. Kipps. Treatment of breast cancer xenografts with paclitaxel enriches for cancer stem cells that can be targeted by a ROR1-specific antibody. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Or