Abstract B58: Connective tissue growth factor (CTGF) as a novel therapeutic target in high grade serous ovarian cancer

Abstract

Abstract The tumor microenvironment plays an active role in promoting proliferation, invasion and metastasis, thereby making soluble factors secreted by cancer-associated fibroblasts promising therapeutic targets. As a result, secreted tumor stromal factors are increasingly being targeted by newly developed anti-cancer therapies. To identify such stromal factors in ovarian cancer, we performed gene expression profiling on microdissected fibroblasts from normal ovary and from high-grade, late stage serous ovarian tumors. We identified a signature of TGFb-regulated genes, over-expressed in cancer-associated fibroblasts, which encode for secreted factors that may serve as potential therapeutic targets. One of these genes, connective tissue growth factor (CTGF), is a secreted protein that promotes proliferation, motility and extracellular matrix production in a number of cancer types. CTGF is currently being pursued as a therapeutic target by FibroGen Inc., who has developed a therapeutic anti-CTGF monoclonal antibody FG-3019. FG-3019 is currently under clinical investigation in pancreatic cancer and fibrotic diseases. To determine the role of CTGF and its potential as a therapeutic target in high-grade serous ovarian cancer (HGSOC), we examined its effect on tumor promotion in ovarian cancer cell lines and associations between CTGF expression and clinico-pathologic characteristics in HGSOC patients. We performed functional studies in SKOV3 and OVCAR3 cell lines using recombinant protein, demonstrating that CTGF promotes anchorage-independent proliferation and migration. These effects of CTGF are blocked by FG-3019. During cancer progression, HGSOC cells from the ovary disseminate and adhere throughout the peritoneal cavity, posing a major challenge in treatment. We and others have shown that mesothelial cells in peritoneal tissue, peritoneal fibroblasts and ovarian cancer omental metastases express CTGF, suggesting that it may be targeted to help prevent recurrence following debulking surgery. To address this, we performed ex-vivo peritoneal adhesion assays, and demonstrate that recombinant CTGF increases a5b1 integrin-mediated adhesion of ovarian cancer cells to peritoneal tissue. In addition, enhancement of peritoneal adhesion by CTGF was blocked upon addition of FG-3019, further supporting its potential as a therapeutic target. In investigating clinico-pathologic characteristics in HGSOC patients, we confirmed over-expression of CTGF in cancer-associated fibroblasts by immunohistochemistry. Furthermore, we found that survival was correlated with CTGF expression, with HGSOC patients expressing the highest levels of tumor stromal CTGF harboring the poorest prognosis. Together, our findings identify and characterize CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in HGSOC. Further studies should investigate the therapeutic efficacy of FG-3019 in combination with platinum/taxane, in HGSOC. Citation Format: Kim Moran-Jones, Rajmohan Murali, David K. Chang, Carol W. Wong, Suzanne M. Spong, Neville F. Hacker, Samuel C. Mok, Michael J. Birrer, Goli Samimi. Connective tissue growth factor (CTGF) as a novel therapeutic target in high grade serous ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B58.