Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada.
Mol Cancer Ther. 2013 Jul;12(7):1245-54. doi: 10.1158/1535-7163.MCT-12-1150. Epub 2013 May 8.
Activating mutations of fibroblast growth factor receptor-3 (FGFR3) have been described in approximately 75% of low-grade papillary bladder tumors. In muscle-invasive disease, FGFR3 mutations are found in 20% of tumors, but overexpression of FGFR3 is observed in about half of cases. Therefore, FGFR3 is a particularly promising target for therapy in bladder cancer. Up to now, most drugs tested for inhibition of FGFR3 have been small molecule, multityrosine kinase inhibitors. More recently, a specific inhibitory monoclonal antibody targeting FGFR3 (R3Mab) has been described and tested preclinically. In this study, we have evaluated mutation and expression status of FGFR3 in 19 urothelial cancer cell lines and a cohort of 170 American patients with bladder cancer. We have shown inhibitory activity of R3Mab on tumor growth and corresponding cell signaling in three different orthotopic xenografts of bladder cancer. Our results provide the preclinical proof of principle necessary to translate FGFR3 inhibition with R3Mab into clinical trials in patients with bladder cancer.
成纤维细胞生长因子受体 3（FGFR3）的激活突变已在约 75%的低级别乳头状膀胱癌中被描述。在肌层浸润性疾病中，FGFR3 突变见于 20%的肿瘤中，但大约一半的病例中观察到 FGFR3 的过表达。因此，FGFR3 是膀胱癌治疗中特别有前途的靶点。到目前为止，大多数针对 FGFR3 抑制作用的测试药物都是小分子多酪氨酸激酶抑制剂。最近，描述并临床前测试了一种针对 FGFR3 的特异性抑制性单克隆抗体（R3Mab）。在这项研究中，我们评估了 19 种尿路上皮癌细胞系和 170 名美国膀胱癌患者队列中 FGFR3 的突变和表达状态。我们已经显示了 R3Mab 在三种不同的膀胱癌原位异种移植中的肿瘤生长和相应的细胞信号抑制作用。我们的结果提供了必要的临床前原理证明，可将 R3Mab 的 FGFR3 抑制作用转化为膀胱癌患者的临床试验。
