Alofanib, an allosteric FGFR2 inhibitor, has potent effects on ovarian cancer growth in preclinical studies

Abstract

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.

FGF/FGFR-Dependent Molecular Mechanisms Underlying Anti-Cancer Drug Resistance

“…Treatment with BGJ398 enhanced the cytotoxic effect of paclitaxel/carboplatin cytotoxic activity in ovarian carcinoma cells [ 208 ]. A similar effect was observed for alofanib, an allosteric FGFR2 inhibitor [ 211 ]. The administration of BGJ398 reduced cell viability and enhanced apoptosis in GIST (gastrointestinal stromal tumor) T-1 cell line resistant to imatinib, but not in parental cells [ 46 ].…”

A cyclic peptide retards the proliferation of DU145 prostate cancer cells in vitro and in vivo through inhibition of FGFR2

“… 18 , 19 Some molecules have been designed to inhibit the activation of FGFR2, however, their performances are not satisfactory enough in clinical and preclinical studies. 20 In our current study, we developed FGFR2‐targeted inhibitory peptide P5, which has been at the same time upgraded to a more stable and effective form (DcP5) through cyclization. Our results highlight that both DcP5 and P5 are potential anticancer agents and cancer‐targeted peptides for FGFR2‐overexpressed malignancies.…”

Signaling Pathway and Small-Molecule Drug Discovery of FGFR: A Comprehensive Review

“…Alofanib (RPT835) belongs to this type of inhibitors and has entered a phase 1 clinical trial in Russia. By specifically binding to IgIII of FGFR2, alofanib is able to inhibit the FGF2-induced phosphorylation of FRS2α with nanomolar activity in cancer cells expressing different FGFR2 isoforms ( Tyulyandina et al, 2017 ). In addition, Tsimafeyeu et al (2016) performed in vivo experiments to demonstrate that alofanib could ablate FGF-induced angiogenesis.…”