Abstract 4223: Rapid identification and targeting of chemotherapy resistant tumor stem cell clones in ovarian high-grade serous carcinoma
Authors: Ting Zhang, Gang Ning, Yusuke Yamamoto, Brooke Howitt, Xia Wang, Lane Wilson, Yue Hong, Chiea Chuen Khor, Suzy Torti, Molly Brewer, Christopher Crum, Frank McKeon, Wa Xian
Journal: Cancer Research (2015)

Abstract The problem of drug resistance has been the bane of cancer management since the advent of chemotherapy. High-grade ovarian cancer is a paradigm of the problem. Although most patients present with advanced disease and, remarkably, show little or no residual tumor after initial reductive surgery and chemotherapy, resistance, emerges over the next six to twelve months in a form that is largely inured to previously effective regimens of carboplatin and paclitaxel. Until now, ovarian cancer researchers remain uncertain about the actual degree of tumor cell heterogeneity before treatment, and whether resistant cells defy chemotherapy by pre-existing genetic difference or acquired mutations. The key technical barrier to addressing these critical questions has been the inability of researchers to generate discrete clones of tumor cells for genomic analysis. Thus, despite the aggressive nature of ovarian cancers, we have only a handful of established cell lines to study. Further, it is often unclear how well these cell lines actually represent their primary tumor of origin. Here we developed and validated a novel technology for the cloning of normal human stem cells from epithelial tissues and have used it to clone “tumor stem cells” from high-grade ovarian cancer. Using this unique stem cell-cloning technology, we tested the hypothesis that the drug-resistant variants pre-exist in primary tumors. Validation of this hypothesis will indicate that effective anti-HGOC therapies must take into account the genetics of the diverse tumor-cell populations within a tumor and target the pre-existing drug-resistant variants. Most importantly, our technology is so robust that it can clone many thousands of individual tumor stem cells from a single tumor. Production of sizeable tumor stem cell “libraries” is critical for our goal to delineate tumor heterogeneity and uncover pre-existing drug-resistant variants that survive the treatment and reemerge as recurrent disease. In preliminary studies, we have shown that we can recapitulate this resistance phenomenon in a tissue-culture dish. For the first time, we can identify these resistant tumor stem cell clones, grow them to large numbers, and fully assess their gene expression and genetic alterations. This gives us a “first look” at the molecular features of the resistant clones that almost certainly cause cancer patients to relapse after apparently successful therapy. The first-ever availability of these tumor stem cell libraries will provide a powerful tool for the discovery of new drugs targeting lethal cells. We believe that it ultimately will alter the way cancer patients are treated and greatly accelerate the rate at which better cancer therapies evolve. Note: This abstract was not presented at the meeting. Citation Format: Ting Zhang, Gang Ning, Yusuke Yamamoto, Brooke Howitt, Xia Wang, Lane Wilson, Yue Hong, Chiea Chuen Khor, Suzy Torti, Molly Brewer, Christopher Crum, Frank McKeon, Wa Xian. Rapid identification and targeting of chemotherapy resistant tumor stem cell clones in ovarian high-grade serous carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4223. doi:10.1158/1538-7445.AM2015-4223