Abstract NT-107: CHEMORESISTANT OVARIAN CANCER STEM CELLS REVEAL NOVEL THERAPEUTIC TARGETS

Abstract

Abstract More than 60% of patients with ovarian cancer respond to first-line therapy, often achieving complete remission. However, these encouraging clinical outcomes are quickly overshadowed by high rates of treatment failure. More than half of advanced-stage patients relapse within five years, and these patients face poor prognoses. We sought to better understand the cause of ovarian cancer treatment failure with the hope of improving patient outcomes. We hypothesized that ovarian cancer stem cells may resist chemotherapy allowing them to regrow tumors causing relapse, metastasis and ultimately death. We further postulated that characterization of these cells would reveal therapeutic targets that may be exploited to achieve more durable remissions. To begin to test this hypothesis, we proposed that high aldehyde dehydrogenase I activity (ALDH1high) would identify stem-like ovarian cancer cells that would resist chemotherapy treatment and be capable of regenerating tumors. We compared ALDH1high cells to ALDH1low cells in three ovarian cancer cell lines: the human SKOV3 cell line, the rat FNAR-C1 cell line, and the murine ID8 cell line. Consistent with our predictions, we found that ALDH1high cells were resistant to several drugs commonly used to treat ovarian cancer. The ALDH1high population was also the only fraction of cells capable of forming tumors in vivo. In keeping with their proposed cancer stem cell phenotype, ALDH1high cells were smaller in size, relatively quiescent, and able to regenerate the phenotypic diversity of the cell line. Furthermore, they lacked contact inhibition and were capable of nonadherent growth. Significant controversy exists concerning how best to identify ovarian cancer stem cells. Many markers have been proposed with data to both support and refute their use in the literature. Resolving these uncertainties is hampered by the lack of systematic evaluation of each marker in proposed cancer stem cell pools. We used microarray analysis and quantitative real-time RT-PCR to measure the expression of ABCG2, CD24, CD44, CD133 and KIT in our ALDH1high cells compared to their ALDH1low counterparts and found no consistent differential regulation in the ALDH1high cells across all three cell lines. Further work remains needed to more clearly define the relationships between each of these proposed ovarian cancer stem cell markers. Gene expression profiles identified several possible vulnerabilities that could be exploited therapeutically. ALDH1high cells have upregulation of the mTOR pathway, FGF18 and CD47. They also express Her-2/neu at similarly high levels as ALDH1low cells. Drugs are already clinically available to target mTOR and Her-2/neu, which would speed their implementation. FGF18 signals through the FGFR3 receptor. Although FGF18 is upregulated in the cancer stem cell pool, both cancer stem and non-stem cells express its receptor, FGFR3, at similar levels. Several approaches to target FGFR3 are in clinical trials, as are antibodies targeting CD47. mTOR and CD47 inhibition would potentially be selective for ovarian cancer stem cells, but Her-2/neu and FGFR3 inhibition could also target the more differentiated, non-stem cancer cells. Further work is necessary to validate these treatment approaches. Citation Format: Allison C. Sharrow, Richard J Jones, Lily Wu. CHEMORESISTANT OVARIAN CANCER STEM CELLS REVEAL NOVEL THERAPEUTIC TARGETS [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-107.