Purpose Early data suggest that combining FGFR2 inhibitors with
platinum-containing
cytotoxic agents for the treatment of
epithelial ovarian cancer may yield increased antitumor activity. We investigated antitumor activity of
alofanib (
RPT835), a novel allosteric FGFR2 inhibitor, in
ovarian cancer in vitro and in vivo. Methods Equal amounts of
ovarian cancer cell (SKOV3) lysates were analyzed for FGFR1-3
protein expression using Wes. To assess the efficacy of
alofanib on FGF-mediated cell proliferation, SKOV3 cells were incubated and were treated with serially diluted
alofanib. 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 SKOV3
cancer cells. 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 31 days after
tumor inoculation. Number of
tumor vessels and Ki-67 index were calculated. Results SKOV3 cells express FGFR1 and FGFR2 but not FGFR3. Basic FGF increased proliferation of the
ovarian cancer cells in untreated control group (P = 0.001).
Alofanib inhibited growth of FGFR2-expressing SKOV3 cells with GI50 value of 0.37 μmol/L. Treatment with
alofanib in combination with
paclitaxel/
carboplatin resulted in
tumor growth delay phenotype in all treatment groups compared to control non-treatment groups. Compound exhibited a dose-dependent effect on
tumor growth. Daily intravenous regimen of
alofanib (total maximum dose per week was 350 mg/kg) demonstrated significant 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 (-49 %; P < 0.0001) and number of Ki-67-positive SKOV3 cells (-42 %, P < 0.05). There were
tumor necrosis and cell degeneration in
alofanib group. Conclusions We suggest that FGFR2 inhibition has potent effects on
ovarian cancer growth in preclinical studies.