UC San Diego

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) plays an important role in embryonic development and is down-regulated after birth. Although ROR1 is not expressed in the majority of normal adult tissues, ROR1 upregulation has been found in cancers. Here, we established five breast cancer patient derived xenografts in mice to investigate whether ROR1-expressing cells display cancer stem cell (CSC) features of sphere formation, invasion, and increased tumorigenicity and whether UC-961, a humanized anti-ROR1 monoclonal antibody could inhibit those features. We found that ROR1⁺ cells formed 3- to 4- fold more spheres and were 2- to 3-fold more invasive than ROR1⁻ cells. Furthermore, ROR1⁺ cells had tumorigenic cell frequencies that were at least 10 times higher than ROR1⁻ cells. When high ROR1-expressing breast cancer cells were treated with UC-961, the cells were inhibited in their capacity to invade Matrigel, self-renew, and engraft tumors in mice by 2-fold. Because CSCs have been associated with increased chemotherapy resistance and thought to be involved in cancer recurrence, we examined the combined effect of UC-961 and Taxol on breast cancer growth and found that they synergistically inhibit breast cancer cell line growth, self-renewal, and tumor formation. In summary, the data suggests that ROR1 associates with CSC characteristics and that targeting ROR1 with monoclonal antibodies with or without Taxol can provide novel therapeutic strategies for cancer treatment