Abstract 961: Inhibitors of fibrosis and TGF-beta delay tumor xenograft growth and reduce ascites in ovarian cancer models
Authors: Zhang Qing , Hou Xiaonan , Evans Bradley J. , Weroha John J. , Cliby William A. 
Published: July 2017

Background: Most ovarian cancer (OC) patients present with advanced disease and ultimately develop chemo-resistant relapses. Stroma plays a significant role in OC behavior including invasiveness, fibrosis and chemoresistance. TGF-β is important for crosstalk between stroma and cancer cells, and stromal activation in cancer has similarities to matrix remodeling in fibrosis. We have shown that TGF-β and fibrosis-inhibitors can suppress OC cell proliferation, migration and invasion. Such inhibitors are available for clinical use, and we have begun to test their efficacy in OC in vivo.

Methods: Animal experiments were approved by Mayo Clinic IACUC. Intraperitoneal xenograft models were derived from OVCAR8 (5×106) cells (OV8-CDX) or 0.1 gm OC patient tumor tissue (PDX) in NSG mice. OV8-CDX and PDX PH003 (an aggressive, chemoresistant and ascites-prone model) (n=5-10 mice/arm) were treated with 2 agents and compared to untreated controls (C): 1) C vs. the fibrosis inhibitor Pirfenidone (P, 200 mg/kg, BID, provided by Genentech); 2) C vs. TGF-β receptor I inhibitor Galunisertib (G, 75 mg/kg, BID, provided by Eli Lily). Mice were pretreated for 2 days before xenografting and treated for 4 weeks with ultrasound (US) to measure tumor growth. At day (d) 28, we i) collected tumor (OV8-CDX); or ii) observed until progression (PH003, PH053). OV8-CDX tumors were used for target gene analysis.

Results: P treatment delayed tumor growth in OV8-CDX relative to control (C): tumors established in 0/5 (P) vs. 1/5 (C), and 1/5 (P) vs. 4/5 (C) of mice at d14 and d28, respectively. The reduced tumor weight (g) at d28 was also confirmed (0.20±0.10 vs. 0.54±0.23, p=0.02). Similarly, P treatment in PH003 inhibited the tumor growth (tumor area (cm2) at d28: 0.74±0.43 vs. 1.04±0.51, p=0.28), ascites development (volume (ml): 1.14±0.54 vs. 3.37±0.62, p=0.05) and prolonged survival time (p=0.04).

G treatment was also associated with delayed tumor establishment in OV8-CDX relative to C: tumors presented in 0/5 (G) vs. 1/5 (C), and 1/5 (G) vs. 4/5 (C) of mice at d14 and d28, respectively. Associated d28 tumor weight was significantly reduced (0.20±0.10 vs. 0.54±0.23, p=0.02) as well. For PH003, G treatment was associated with delayed tumor growth (tumor area at d28: 0.57±0.27 vs. 1.04±0.51, p=0.05), a marked reduction in ascites (volume: 1.25±0.56 vs. 3.37±0.62, p=0.05) and a prolonged survival time (p=0.04)

We identified down-regulation of TGF-β signaling-related genes (e.g. TGFB1, TGFBR2) and fibrosis-related biomarkers (e.g. FAP, COL11A1) following drug treatment confirming inhibition of relevant pathways.

Conclusion: We report that 2 currently available inhibitors targeting either fibrosis or TGF-β appear to have efficacy in vivo and delay tumor growth in OC PDX models. These results suggest promise for a strategy of targeting the stromal component of OC.

Citation Format: Qing Zhang, Xiaonan Hou, Bradley J. Evans, John J. Weroha, William A. Cliby. Inhibitors of fibrosis and TGF-beta delay tumor xenograft growth and reduce ascites in ovarian cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 961. doi:10.1158/1538-7445.AM2017-961