Fibroblast growth factor receptor 3 is a rational therapeutic target in bladder cancer.
Fibroblast growth factor receptor 3 is a rational therapeutic target in bladder cancer.
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DOI：
10.1158/1535-7163.mct-12-1150
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发表时间：
2013-07
影响因子：
5.7
通讯作者：
Black PC
中科院分区：
文献类型：
--
作者：
Gust KM;McConkey DJ;Awrey S;Hegarty PK;Qing J;Bondaruk J;Ashkenazi A;Czerniak B;Dinney CP;Black PC
成纤维细胞生长因子受体-3（FGFR 3）的激活突变已在约75%的低度乳头状膀胱肿瘤中描述。在肌肉浸润性疾病中，在20%的肿瘤中发现了FGFR 3突变，但在约一半的病例中观察到FGFR 3过表达。因此，FGFR 3是膀胱癌治疗的特别有前途的靶标。到目前为止，大多数用于抑制FGFR 3的药物都是小分子、多酪氨酸激酶抑制剂。最近，已经描述了靶向FGFR 3的特异性抑制性单克隆抗体（R3 Mab）并进行了临床前测试。在这项研究中，我们评估了19个尿路上皮癌细胞系和170个美国膀胱癌患者队列中FGFR 3的突变和表达状态。我们在三种不同的膀胱癌原位异种移植物中证明了R3 Mab对肿瘤生长和相应细胞信号传导的抑制活性。我们的研究结果提供了将R3 Mab抑制FGFR 3转化为膀胱癌患者临床试验所需的临床前原理证明。
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, multi-tyrosine kinase inhibitors. More recently, a specific inhibitory monoclonal antibody targeting FGFR3 (R3Mab) has been described and tested pre-clinically. In this study, we have evaluated mutation and expression status of FGFR3 in 19 urothelial cancer cell lines and a cohort of 170 American bladder cancer patients. We demonstrated inhibitory activity of R3Mab on tumor growth and corresponding cell signaling in three different orthotopic xenografts of bladder cancer. Our results provide the pre-clinical proof of principle necessary to translate FGFR3 inhibition with R3Mab into clinical trials in patients with bladder cancer.