Rabbit Anti-Human FGFR2 monoclonal antibody, clone TQ384

Patients with poorly differentiated endometrial cancer show poor prognosis, and effective molecular target-based therapies are needed. Endometrial cancer cells proliferate depending on the activation of HES1 (hairy and enhancer of split-1), which is induced by several pathways, such as the Notch and fibroblast growth factor receptor (FGFR) signaling pathways. In addition, aberrant, ligand-free activation of the FGFR signaling pathway resulting from mutations in FGFR2 was also reported in endometrial cancer. However, a clinical trial showed that there was no difference in the effectiveness of FGFR inhibitors between patients with and without the FGFR2 mutation, suggesting a presence of another signaling pathway for the FGFR activation. Here, we investigated the signaling pathway regulating the expression of HES1 and proliferation of poorly and well-differentiated endometrial cancer cell lines Ishikawa and HEC-50B, respectively. Whereas Ishikawa cells proliferated and expressed HES1 in a Notch signaling-dependent manner, Notch signaling was not involved in HES1 and proliferation of HEC-50B cells. The FGFR inhibitor, NVP-BGJ398, decreased HES1 expression and proliferation of HEC-50B cells; however, HEC50B cells had no mutations in the FGFR2 gene. Instead, HEC-50B cells highly expressed ligands for FGFR2, suggesting that FGFR2 is activated by an autocrine manner, not by ligand-free activation. This autocrine pathway activated Akt downstream of FGFR for cell proliferation. Our findings suggest the usefulness of HES1 as a marker for the proliferation signaling and that FGFR inhibitor may be effective for poorly differentiated endometrial cancers that harbor wild-type FGFR.

Important advances in the understanding of the biology and mechanisms of tumor progression of urothelial carcinoma (UC) have been achieved over the past decade. The treatment landscape for advanced-stage, unresectable or metastatic UC has shifted dramatically over a short period of time, with 6 new therapeutic agents available for clinical use. The use of traditional chemotherapy and new immune checkpoints inhibitors (ICIs) directed at programmed cell-death protein 1 (PD-1) or its ligand has led to unprecedented survival benefits in selected patients with metastatic UC. Data show that anti-PD-1 ICIs are not only improving long-term clinical benefit, but also quality of life for patients in the second-line setting. In the front-line setting, regulatory agencies have restricted the indications of atezolizumab and pembrolizumab (both ICIs) to patients with PD-L1positivity with advanced UC and who are platinum-ineligible. Very recently, erdafitinib, a pan-FGFR inhibitor, has been granted accelerated approval by FDA for platinum-pretreated advanced metastatic UC with susceptible FGFR3 or FGFR2 genetic alterations. Enfortumab vedotin, an antibody-drug conjugate, have been granted breakthrough designation by the FDA for the treatment of metastatic UC. Here we review the clinical trial data that have established standard-of-care treatment for advanced-stage UC. In addition, mechanisms of resistance and biomarkers of response to platinum-based chemotherapies and immunotherapies are also discussed, along with the clinical benefits and limitations of these therapies.