Abstract NT-115: PRE-EXISTENCE OF POLY-RESISTANT CANCER STEM CELLS IN HIGH-GRADE OVARIAN CANCER

INTRODUCTION: High-grade ovarian cancer (HGOC) shows excellent responses to standard-of-care surgery and paclitaxel/carboplatin therapy only to relapse 6-24 months later with typically resistant disease. While the origin of this recurrent, resistant disease is unclear, most believe it is acquired by the action of chemotherapeutics. Using novel stem cell technology that enables the cloning of cancer stem cells (CSCs) from epithelial cancers, we have generated large libraries of CSCs from multiple cases of HGOC. And while the vast majority of these CSC clones are killed by standard-of-care chemotherapeutic drugs, a minor fraction shows profound resistance not only to paclitaxel/carboplatin but to a wide range of structurally unrelated chemotherapeutic drugs to which these cells had no prior exposure. We describe screens for drugs that selectively target this resistant CSC population. METHODS: Libraries of 10- to 100,000 CSC clones were generated from individual, therapy naive, HGOC resections using technology we developed for cloning so-called “adult” stem cells from normal columnar epithelia (Wang et al., 2015, Nature, 522, 173). RESULTS: Paclitaxel/carboplatin resistant CSCs were identified in CSC libraries derived from therapy naive tumors at ratios of 1:50 to 1:300. By copy number variation, these resistant variant clones proved distinct from the bulk of CSCs, and by gene expression analysis varied from sensitive clones by more than 700 differentially expressed genes. Independent resistant clones from the same library clustered with other resistant clones by both copy number variation and gene expression profiles, suggesting the possibility that resistance within a single tumor is dominated by a single type of resistant CSCs. Clones resistant to paclitaxel/carboplatin were screened in a 384-well format against a wide range of experimental drug-like molecules. These pre-existing resistant clones also proved to be profoundly resistant to a large number of structurally unrelated chemotherapeutic drugs. This same screening program identified drugs that act alone or in combination with paclitaxel to eliminate these resistant clones, suggesting a route to personalized medicine for addressing the problem of recurrent disease in HGOC. CONCLUSIONS: Tumors from patients with HGOC possess clonogenic CSCs including variants that are resistant to a broad spectrum of chemotherapeutics to which they have not been exposed. It is likely that such CSCs would survive standard-of-care chemotherapy and contribute to the recurrent disease seen in HGOC. We have identified known and experimental drugs that specifically eliminate these resistant variants and the overall platform represents a potential strategy to addressing the problem of recurrent disease in these patients. Citation Format: Jingzhong Xie, Yusuke Yamamoto, Marcin Duleba, Bailiang Wang, Rajasekaran Mahalingam, Shan Wang, Wei Rao, Suchan Niroula, Clifford Stephan, Peter Davies, Amir Jazaeri, Giulio Draetta, Molly Brewer, Matt L. Anderson, Christopher P. Crum, Frank McKeon, and Wa Xian. PRE-EXISTENCE OF POLY-RESISTANT CANCER STEM CELLS IN HIGH-GRADE OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-115.