Abstract 3244: Treatment of endometrial cancer cells with a new small tyrosine kinase inhibitor targeting mutated fibroblast growth factor receptor-2

Abstract

Abstract Endometrial cancer (EC) is the most common uterine malignancy in industrialized countries and is the most frequent gynecologic cancer in the United States with an estimated 60,050 new cases in 2016. Traditionally observed in peri-, postmenopausal women, the incidence rate of EC has steadily increased among younger women of reproductive age over the past two decades partially owing to a more sedentary lifestyle and rampant obesity epidemic. Surgery in combination with either radio- and or chemotherapy is commonly curative for the early stage of the disease. However, patients with recurrent or metastatic disease, who only respond poorly to cytotoxic chemotherapy are in desperate need of therapeutic alternatives as are patients of reproductive age. Thus, innovative, safe and more effective therapies are mandated. Several studies have demonstrated the increased expression of various tyrosine kinase receptors involved in the development of EC. We hypothesized that a targeted therapeutic approach using a pan-tyrosine kinase inhibitor would prevent the proliferation and progression of EC. Anlotinib (AL3818) is a multi-targeted receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors 1 to 3 (VEGFR1-3), stem cell factor receptor (C-kit), platelet-derived growth factor (PDGFβ), and fibroblast growth factor receptors 1 to 3 (FGFR1-3). We tested a panel of seven human endometrial cancer cell lines (AN3Ca, Ishikawa, HEC1A, HEC1B, KLE, MFE280 and MFE296) to assess the cytotoxicity of anlotinib in vitro. A lower IC50 value was observed in AN3Ca cells (25 nM), a cell line characterized by a high level of expression of an FGFR2 mutant protein, while cell lines expressing FGFR2 wild-type are less sensitive to anlotinib (HEC1A: 33 μM, or HEC1B:36 μM). Somatic mutations of FGFR2 have been observed in 12% of EC, indicating the potential for this drug in a subset of EC patients. In summary, these results suggest improved efficacy of anlotinib for the treatment of ECs expressing an increased level of FGFR2 mutant proteins. The safety and efficacy of anlotinib are currently being evaluated in an orthotopic AN3Ca mouse model of EC. Experimental groups include a tumor bearing control not subjected to any treatment, anlotinib alone, carboplatin/paclitaxel, a combination of anlotinib and carboplatin/paclitaxel. Primary study endpoints include tumor growth retardation, the delayed onset of local metastases as well as reduced toxicity as secondary endpoint. Citation Format: Sebastien Taurin, Chieh-Hsiang Yang, Maria Reyes, Sungpil Cho, Elke A. Jarboe, Theresa L. Werner, Demetrius M. Coombs, Paul Chen, Margit M. Janát-Amsbury. Treatment of endometrial cancer cells with a new small tyrosine kinase inhibitor targeting mutated fibroblast growth factor receptor-2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3244. doi:10.1158/1538-7445.AM2017-3244