Endometrioid endometrial carcinoma is the most common form of uterine cancer in the United States. Despite an overall good prognosis, mortality for advanced stage or recurrent endometrioid endometrial cancers is high. Cytotoxic agents (doxorubicin, cisplatin, paclitaxel) have had limited success in the treatment of aggressive endometrial cancer. There is a clear need for additional adjuvant therapies that can be used alone or in combination with currently available treatment modalities. We identified activating mutations in FGFR2 in 16% (18/116) of endometrioid endometrial tumors. Preliminary analysis shows that. FGFR2 mutation status approaches significance (p~0.07) in contributing to an increase in the odds of recurrence (OR=4.2, Cl. 0.98-20) in low risk early stage endometrial cancer patients. We hypothesize that FGFR2 may be viable therapeutic target in endometrial cancer. This hypothesis is further supported by our finding that endometrial cancer cell lines with mutant FGFR2 are 10-40x more sensitive to FGFR inhibition than cell lines expressing wild type FGFR2, with FGFR inhibition exhibiting both cytostatic and cytotoxic activity. We propose to validate the role FGFR2 mutations play in low risk early stage endometrial cancers by sequencing 1572 endometrioid tumors linked to detailed clinical data collected as part ofthe NCI-funded Gynecologic Oncology Group (GOG) protocol, GOG-210, and evaluating the relationship between FGFR2 mutation status and clinicopathologic variables including disease-free and overall survival. We further aim to investigate the prevalence of additional mechanisms of FGFR activation in this data set, including receptor overexpression and/or the establishment of an autocrine loop by ectopic expression of cognate ligands within the tumor. We will examine the expression of FGFR2 and its cognate ligands on several TMAs constructed using GOG-210 tumor samples and will determine the relationship between expression of FGF ligands and receptors and clinicopathologic variables including outcome. We also aim to elucidate the rholecular mechanisms involved in cell cycle arrest and cell death following treatment with the FGFR inhibitors PDI 73074 and BMS582664. Finally we propose to test the dual VEGFR/FGFR inhibitor BMS582664 in a Phase II human clinical trial comprising up to 60 patients enrolled to represent both mutation positive and negative tumors. This study will be performed through the NCI sponsored GOG. Successful completion of these studies will identify the prevalence of activated FGFR2 in endometrioid endometrial tumors and the impact of activated FGFR2 on clinicopathologic variables. Completion of a Phase II clinical trial with BMS582664 could facilitate the introduction of a targeted therapeutic agent into the treatment of endometrial cancer and thus have a major impact on the clinical management of this disease.
The work proposed will lead to both an improved understanding of endometrial cancer biology and new approaches to the detection, prevention and treatment of uterine cancers which will result in reduced cancer morbidity and mortality.
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