Abstract 796: Alofanib, a novel allosteric FGFR2 inhibitor, shows potent antitumor activity in ovarian cancer with FGFR2 expression

Abstract

Abstract Alofanib (formerly known as RPT835) is a novel allosteric FGFR2 inhibitor with activity in FGFR2-expressing triple-negative breast cancer [Tjulandin S, et al. San Antonio Breast Cancer Symposium 2014]. Early data suggest that combining FGFR2 inhibitors with platinum-containing cytotoxic agents for the treatment of epithelial ovarian cancer may yield increased antitumor activity [Cole C, et al. Cancer Biol Ther. 2010]. We investigated antitumor activity of alofanib in ovarian cancer in vitro and in vivo. To assess the efficacy of alofanib on FGF-mediated cell proliferation, ovarian cancer (SKOV-3) FGFR2-expressing cells were incubated in a 96-well microculture plate and were treated with serially diluted RPT835. Basic FGF was added at a concentration of 25 ng/ml. Control wells were left untreated. Cell growth inhibition was determined using Promega's Cell Titer-Glo® assay. Immunocompromised mice were used for xenotransplantation of FGFR2 high-expressing ovarian cancer cells (SCOV-3). Seventy animals with measurable tumors were selected on day 10 and randomized into control groups (no treatment or chemotherapy alone (paclitaxel + carboplatin) and treatment groups (alofanib orally or intravenously (different dose levels) in combination with chemotherapy). Measurements of tumor volume (mm3) were performed by digital calipers every 3 days during 30 days after tumor inoculation. Basic FGF significantly increased proliferation of the ovarian cancer cells in untreated control group (P = 0.001). Alofanib treatment resulted in growth inhibition of SKOV-3 cell line in vitro. Treatment of alofanib in combination with paclitaxel/carboplatin demonstrated significant tumor growth delay phenotype in all treatment groups compared to control non-treatment groups. Alofanib exhibited a dose-dependent effect on tumor growth. Daily intravenous regimen of alofanib (total maximum dose per week was 350 mg/kg) demonstrated dramatic effect (inhibiting growth by 80% and by 53% in comparison with vehicle and chemotherapy group alone, respectively (P<0.001). Alofanib decreased number of vessels in tumor on 49% compared with chemotherapy alone (P<0.05). There were tumor necrosis and cell degeneration in alofanib group. These results provide strong rationale for evaluation of alofanib in combination with paclitaxel and carboplatin in patients with ovarian cancer. Citation Format: Sergei Tjulandin, Mikhail Byakhov, Evgenia Stepanova, Dmitry Khochenkov, Daniel Harrison, Ilya Tsimafeyeu. Alofanib, a novel allosteric FGFR2 inhibitor, shows potent antitumor activity in ovarian cancer with FGFR2 expression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 796. doi:10.1158/1538-7445.AM2015-796