Abstract POSTER-THER-1420: Ascites drives ovarian cancer stem-like cell growth: therapeutic opportunities
Mo, L; Kennedy, M; Berchuck, A; Cianciolo, G; Bachelder, RE; Pizzo, SV
Published in: Clinical Cancer Research
Background: A significant literature suggests that cancer stem-like cells drive the aggressive behavior of ovarian cancer. Cancer stem-like cells are distinct from bulk tumor cells in possessing self-renewing/tumor-initiating activity and exhibiting therapy resistance. Accordingly, targeting cancer stem-like cells is a logical approach to developing an effective ovarian cancer therapy.The presence of ascites in ovarian cancer patients is associated with decreased five-year survival. Ascites promotes anti-apoptotic signaling in ovarian cancer cells. However, an ability of ascites to drive cancer stem-like behavior has not been tested.Glucose-regulated protein of 78 kDa (GRP78) is expressed on the surface of a variety of tumor types. This receptor is an ideal therapeutic target because it promotes tumor cell survival(Li and Lee, 2006) and is not detected in normal tissues. In head and neck cancer, cell surface GRP78-positive tumor cells exhibit cancer stem-like behaviors (Wu et al., 2010. Mol Cancer. 9:283.). However, it remains unknown if targeting cell surface GRP78 is an efficient strategy for killing cancer stem-like cells.We have produced and characterized a unique set of monoclonal antibodies specific for the carboxy-terminus (C-terminus) of GRP78. These antibodies inhibit Akt signaling and suppress melanoma growth (Misra et al. , 2010. Cancer biology & therapy. 9:142-152; de Ridder et al. 2012. Melanoma Res. 22:225-235). Neither the ability of these antibodies to target cancer stem-like cells, nor their therapeutic potential for ovarian cancer has been previously assessed.Purpose of the current studies: 1) Address the hypothesis that ascites fluid enriches for therapy-resistant ovarian cancer stem-like cells, 2) Determine efficacy of targeting cell surface GRP78 to eliminate ascites-enriched ovarian cancer stem-like cells.Experimental Procedures: Ovarian cancer cells (murine and human) were incubated with acellular ascites fluid obtained from an ovarian cancer mouse model or from ovarian cancer patients. Ability of these cells to grow as self-renewing spheres in vitro and to initiate tumor growth in a mouse model were measured. Stem cell marker (CD133, Oct4) and cell surface GRP78 expression were assessed by flow cytometry. Effects of anti-GRP78 antibodies on cancer stem-like cell behaviors in vitro and on tumor growth in vivo were measured.Data Summary: Incubation of ovarian cancer cells with ascites enriched for tumor cells with increased self-renewing/tumor initiating activity and increased cell surface GRP78 expression. A C-terminal anti-GRP78 antibody suppressed ascites-enriched ovarian cancer stem-like cells by inhibiting Akt signaling. Ovarian cancer bearing mice receiving the C-terminal anti-GRP78 antibody survived significantly longer than those receiving an IgG control.Conclusions: Acellular ascites fluid enriches for therapy-resistant cancer stem-like cells that express cell surface GRP78. An antibody specific for the C-terminus of GRP78 suppresses ascites-enriched ovarian cancer stem-like cells. We are currently testing the ability of this antibody to increase chemotherapy sensitivity of ovarian cancer by eliminating therapy-resistant cancer stem-like cells. These studies are expected to lay the groundwork for future clinical trials investigating if a humanized form of this anti- GRP78 antibody +/- chemotherapy reduces incidence of ovarian cancer mortality.Citation Format: Lihong Mo, Margaret Kennedy, Andrew Berchuck, George Cianciolo, Robin E. Bachelder, Salvatore V. Pizzo. Ascites drives ovarian cancer stem-like cell growth: therapeutic opportunities [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1420.
