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.
Department of Clinical Pharmacology and Chemotherapy, N.N. Blokhin Russian Cancer Research Center, Moscow, Russia.
Alexandra
A
Tyulyandina
Altogen Labs, Austin, TX, USA.
Daniel
D
Harrison
Altogen Labs, Austin, TX, USA.
Wei
W
Yin
Laboratory of biomarkers and mechanisms of tumor angiogenesis, N.N. Blokhin Russian Cancer Research Center, Moscow, Russia.
Evgenia
E
Stepanova
Laboratory of biomarkers and mechanisms of tumor angiogenesis, N.N. Blokhin Russian Cancer Research Center, Moscow, Russia.
Dmitry
D
Kochenkov
Laboratory of biomarkers and mechanisms of tumor angiogenesis, N.N. Blokhin Russian Cancer Research Center, Moscow, Russia.
Eliso
E
Solomko
Laboratory of biomarkers and mechanisms of tumor angiogenesis, N.N. Blokhin Russian Cancer Research Center, Moscow, Russia.
Nina
N
Peretolchina
FD Computing, Beerse, Belgium.
Frits
F
Daeyaert
EcoSynth, Oostende, Belgium.
Jean-Baptiste
JB
Joos
EcoSynth, Oostende, Belgium.
Koen
K
Van Aken
Moscow Clinical and Research Center, Moscow, Russia.
Mikhail
M
Byakhov
Ruspharmtech LLC, Griboyedov canal nab. 130 Liter A, off. 202, Saint Petersburg, 190121, Russia.
Evgenia
E
Gavrilova
Department of Clinical Pharmacology and Chemotherapy, N.N. Blokhin Russian Cancer Research Center, Moscow, Russia.
Sergei
S
Tjulandin
Ruspharmtech LLC, Griboyedov canal nab. 130 Liter A, off. 202, Saint Petersburg, 190121, Russia. tsimafeyeu@ruspharm.com.
Ilya
I
Tsimafeyeu
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D016190:Carboplatin / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D047368:Tumor Burden / Q000187:drug effects
D000970:Antineoplastic Agents; D001565:Benzoates; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D016190:Carboplatin; C496348:FGFR1 protein, human; C496353:FGFR2 protein, human; C496365:FGFR3 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3; C000610985:alofanib; D017239:Paclitaxel
Allosteric inhibitor; Alofanib; FGFR2; Ovarian cancer; Preclinical studies; RPT835