Epithelial ovarian cancer, or EOC, is one of the leading causes of cancer related death in women. The primary treatments for EOC revolve around surgical removal of the tumor followed by administration of one or more chemotherapeutic drugs.
One of the chemotherapy targets is the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase family. VEGF is important for angiogenesis and has been shown to stimulate cellular migration in vitro. Overexpression has been linked to progression in ovarian cancers. One of a new generation of drugs targeting this kinase is axitinib. Axitinib is a small molecule drug that inhibits VEGFR tyrosine kinases 1, 2, and 3. Shown previously to potentially prevent angiogenesis and promote apoptosis in cancer cells, it is currently a treatment for renal cell carcinomas. Phase 2 trials with axitinib on a variety of solid tumors have also shown positive results. E Sun Paik, Tae-Hyun Kim, and Young Jae Cho proceeded to conduct pre-clinical testing on axitinib’s effectiveness against epithelial ovarian cancer, saying “We hypothesize that axitinib inhibits EOC cells by targeting multiple pathways including angiogenesis, AKT, and ERK phosphorylation”.
Starting with in vitro studies, the group began by testing axitinib’s anti-cancer activity on a set of EOC cell lines including A2780, RMG1, HeyA8, and its drug resistant variant HeyA8-MDR. Measuring active Caspase-3 activity, the group found that axitinib seemed to induce apoptosis in a dose dependent manner as well as decrease cell viability in all cell lines. Following up by measuring levels of VEGFR, and the phosphorylated versions of ERK and AKT, it was found that the all lines except HeyA8-MDR had decreased levels of p-VEGFR, p-ERK, and p-AKT inferring decreased cellular proliferation. Follow up cell migration assays affirmed the VEGFR test, showing that A2780 and HeyA8 had decreased migration abilities where HeyA8-MDR had no significant change compared to controls. These in vitro assays seem to point to axitinib having anti-cancer activity against EOC lines, except in the case of drug resistant variants.
The group then began in vivo testing, implanting EOC lines A2780, RMG1, and HeyA8-MDR into mice and treating them with axitinib. It was found that after 7 days, tumors from A2780 and RMG1 had halved in weight compared to controls, while HeyA8-MDR did not show significant changes compared to controls. They then confirmed the previous in vitro cell proliferation and apoptosis results using Ki-67 staining to measure proliferation and TUNEL assays to measure apoptosis showing again that the drug resistant HeyA8-MDR showed no change with axtinib treatment.
The group continued the testing, using three patient derived xenografts (PDX), with one heavily pre-treated and platinum resistant carcinoma model. Upon treatment with axitinib, only the drug resistant model did not respond to axitinib, while the others having significantly decreased tumor weight. This was confirmed again with Ki-67 staining and TUNEL assays agreeing with both the in vitro and in vivo tests.
The group summed up their results by concluding that the “anti-tumor effects of axitinib as a single agent were significant only in drug-sensitive EOC models but were not remarkable in drug-resistant EOC cell line xenograft or PDX models”. Axitinib is already an FDA approved treatment for renal cell carcinomas, and this work shows it might also be effective in the treatment of epithelial ovarian cancer.
Sources: Scientific Reports, OncLiveTV
