Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors
Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors
复制标题
DOI：
10.1073/pnas.1120068109
复制
发表时间：
2012-07-17
影响因子：
11.1
通讯作者：
Hoey, Timothy
中科院分区：
文献类型：
--
作者：
Gurney, Austin;Axelrod, Fumiko;Hoey, Timothy
Wnt/β-catenin途径通过FrizzledFzd受体家族和几个辅助受体传递信号，长期以来一直与癌症有关。在这里，我们展示了一种用单抗OMP-18R5靶向Wnt通路的治疗方法。这种抗体最初是通过与Frizzled7结合而鉴定的，它通过胞外区的一个保守表位与五个Fzd受体相互作用，并阻断由多个Wnt家族成员诱导的规范Wnt信号。在对最小传代的人类肿瘤进行的异种移植研究中，这种抗体可以抑制一系列肿瘤类型的生长，降低肿瘤启动细胞的频率，并显示出与标准护理化疗药物的协同活性。
The Wnt/beta-catenin pathway, which signals through the Frizzled (Fzd) receptor family and several coreceptors, has long been implicated in cancer. Here we demonstrate a therapeutic approach to targeting the Wnt pathway with a monoclonal antibody, OMP-18R5. This antibody, initially identified by binding to Frizzled 7, interacts with five Fzd receptors through a conserved epitope within the extracellular domain and blocks canonical Wnt signaling induced by multiple Wnt family members. In xenograft studies with minimally passaged human tumors, this antibody inhibits the growth of a range of tumor types, reduces tumor-initiating cell frequency, and exhibits synergistic activity with standard-of-care chemotherapeutic agents.