Abstract 206: Depletion of ovarian cancer initiating cells by a monoclonal antibody against ROR1

Abstract

Abstract ROR1 is a type I orphan-receptor tyrosine-kinase-like surface protein that is expressed during embryogenesis and by various cancer cells, but not on normal adult tissues. Its expression is associated with less-well-differentiated tumors with high metastatic potential (Zhang et al Am J Pathol, 2012, PMCID 3509760; Cui et al Cancer Res, 2013, PMCID 3832210). We evaluated the expression of ROR1 in human ovarian cancers and examined the activity of newly developed anti-ROR1 monoclonal antibodies (mAbs, e.g. UC-961) found to have activity against ROR1-expressing breast cancer cell lines and B-cell leukemias. We examined primary human ovarian cancer cells engrafted into immune-deficient NOD/scid mice (PDX) for human ROR1 expression and for phenotypic and functional characteristics of cancer-stem cells (CSC). In each tumor specimen, we observed different proportions of ROR1-expressing cells. Expression of ROR1 associated with markers of CSC, such as aldehyde dehydrogenase 1 (ALDH1). Moreover, the ROR1+ cells from any given PDX sample had a greater capacity to form spheroids in vitro and to engraft immune-deficient mice than did ROR1-negative cells isolated from the same tumor population. Treatment of ovarian cancer cells with the anti-ROR1 mAb UC-961, but not control IgG, reproducibly impaired their ability to form spheroids, and to engraft into immune-deficient NOD/scid mice. In subsequent studies, we isolated ALDH1+ and ALDH1- cells from the same PDX samples. As noted in prior studies (Ginestier et al Cell Stem Cell, 2007, PMCID 2423808), ALDH1+ cells engrafted more effectively than ALDH1- cells. However, treatment of ovarian cancer cells with the UC-961 mAb abrogated the difference in the capacity of ALDH1+ versus ALDH1- cells to engraft NOD/scid mice. Analysis of the few tumors that did develop in mice engrafted with UC-961-treated, but not control IgG-treated, tumor cells revealed that, compared to the original PDX tumor sample, these tumors had lower proportions of ALDH1+ cells and reduced expression of the polycomb ring finger oncogene, BMI1, and changed the expression level of markers associated with the epithelial-mesenchymal transition (e.g. E-Cadherin and vimentin). Collectively, these studies indicate that expression of ROR1 is associated with CSC and that anti-ROR1 mAbs such as UC-961 can interfere with CSC function and self-renewal, suggesting that such biologics may be useful in the treatment of patients with ovarian cancer. Citation Format: Suping Zhang, Bing Cui, Hsien Lai, Grace Liu, Christina Wu, George Widhopf, Rongrong Wu, Fitzgerlad Lao, Richard Schwab, Dennis Carson, Thomas J. Kipps. Depletion of ovarian cancer initiating cells by a monoclonal antibody against ROR1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 206. doi:10.1158/1538-7445.AM2014-206