Inhibition of AXL and VEGF-A Has Improved Therapeutic Efficacy in Uterine Serous Cancer

SIMPLE SUMMARY: Uterine serous cancer (USC) is an aggressive form of endometrial cancer. USC constitutes less than 10% of endometrial cancer cases but is responsible for up to 40% of endometrial cancer deaths. Response to standard platinum and taxane therapy is modest, particularly in the recurrent setting. Thus, novel therapeutic strategies are needed to overcome this drug resistance. We hope that our findings provide strong preclinical support for the combination of an AXL inhibitor with bevacizumab in USC clinical trials in the recurrent setting. ABSTRACT: Endometrial cancer remains the most prevalent gynecologic cancer with continued rising incidence. A less common form of this cancer is uterine serous cancer, which represents 10% of endometrial cancer cases. However, this is the most aggressive cancer. The objective was to assess whether inhibiting the receptor tyrosine kinase AXL with AVB-500 in combination with bevacizumab would improve response in uterine serous cancer. To prove this, we conducted multiple angiogenesis assays including tube formation assays and angiogenesis invasion assays. In addition, we utilized mouse models with multiple cells lines and subsequently analyzed harvested tissue through immunohistochemistry CD31 staining to assess microvessel density. The combination treatment arms demonstrated decreased angiogenic potential in each assay. In addition, intraperitoneal mouse models demonstrated a significant decrease in tumor burden in two cell lines. The combination of AVB-500 and bevacizumab reduced tumor burden in vivo and reduced morphogenesis and migration in vitro which are vital to the process of angiogenesis.