Alofanib, an allosteric FGFR2 inhibitor, has potent effects on ovarian cancer growth in preclinical studies
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.
KeywordsAlofanib RPT835 FGFR2 Allosteric inhibitor Ovarian cancer Preclinical studies
Compliance with ethical standards
Conflict of interest
I. Tsimafeyeu, M. Byakhov and S. Tjulandin have ownership interest in Ruspharmtech LLC. Evgenia Gavrilova is an employee of Ruspharmtech LLC.
These studies were supported by a grant from Skolkovo Foundation.
All applicable international and institutional guidelines for the care and use of animals were followed.
- 3.Scully R, Young RH, Clement PB (1998) Surface epithelial-stromal tumors and serous tumors. In: Tumors of the ovary, maldeveloped gonads, fallopian tube, and broad ligament. District of Columbia: Armed Forces Institute of Pathology, Washington, p. 51Google Scholar
- 4.NCCN Clinical Practice Guidelines. Ovarian cancer ver.1 2016 https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf
- 6.Tsimafeyeu I, Khasanova A, Stepanova E, Gordiev M, Khochenkov D, Naumova A et al (2016) FGFR2 overexpression predicts survival outcome in patients with metastatic papillary renal cell carcinoma. Clin Transl Oncol 5 [Epub ahead of print]. doi: 10.1007/s12094-016-1524-y
- 8.Tyulyandina A, Tsimafeyeu I, Demidova I, Gikalo M, Tjulandin S FGFR2 amplification in serous ovarian cancer. Cancer Res 76(14 Supplement):4586–4586Google Scholar
- 15.Garcia AA, Hirte H, Fleming G, Yang D, Tsao-Wei DD, Roman L et al (2008) Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret hospital phase II consortia. J Clin Oncol 26:76–82CrossRefPubMedGoogle Scholar