University of Melbourne & Victorian Infectious Diseases Reference Laboratory, Doherty Institute of Infection and Immunity, Melbourne, Victoria, Australia.
Institute of Medical Biology, Singapore, Singapore.
Cancer Res. 2019 Mar 1;79(5):970-981. doi: 10.1158/0008-5472.CAN-18-2095. Epub 2019 Jan 8.
A subset of patients with gastric cancer have mutations in genes that participate in or regulate Wnt signaling at the level of ligand (Wnt) receptor (Fzd) binding. Moreover, increased Fzd expression is associated with poor clinical outcome. Despite these findings, there are no studies investigating the potential of targeting Wnt receptors for treating gastric cancer, and the specific Wnt receptor transmitting oncogenic Wnt signaling in gastric cancer is unknown. Here, we use inhibitors of Wnt/Fzd (OMP-18R5/vantictumab) and conditional gene deletion to test the therapeutic potential of targeting Wnt signaling in preclinical models of intestinal-type gastric cancer and organoid cultures. Pharmacologic targeting of Fzd inhibited the growth of gastric adenomas . We identified Fzd7 to be the predominant Wnt receptor responsible for transmitting Wnt signaling in human gastric cancer cells and mouse models of gastric cancer, whereby Fzd7-deficient cells were retained in gastric adenomas but were unable to respond to Wnt signals and consequently failed to proliferate. Genetic deletion of or treatment with vantictumab was sufficient to inhibit the growth of gastric adenomas with or without mutations to . Vantictumab is currently in phase Ib clinical trials for advanced pancreatic, lung, and breast cancer. Our data extend the scope of patients that may benefit from this therapeutic approach as we demonstrate that this drug will be effective in treating patients with gastric cancer regardless of mutation status. SIGNIFICANCE: The Wnt receptor Fzd7 plays an essential role in gastric tumorigenesis irrespective of mutation status, therefore targeting Wnt/Fzd7 may be of therapeutic benefit to patients with gastric cancer.
一部分胃癌患者存在参与或调节配体（Wnt）受体（Fzd）结合水平 Wnt 信号的基因突变。此外，Fzd 表达增加与不良临床结局相关。尽管有这些发现，但目前尚无研究探讨针对 Wnt 受体治疗胃癌的潜力，且在胃癌中传递致癌 Wnt 信号的特定 Wnt 受体也尚不清楚。在这里，我们使用 Wnt/Fzd（OMP-18R5/vantictumab）抑制剂和条件基因缺失来测试针对肠型胃癌的临床前模型和类器官培养物中 Wnt 信号的治疗潜力。Fzd 的药理靶向抑制了胃腺瘤的生长。我们确定 Fzd7 是负责在人类胃癌细胞和胃癌小鼠模型中传递 Wnt 信号的主要 Wnt 受体，其中 Fzd7 缺陷细胞在胃腺瘤中保留，但无法响应 Wnt 信号，因此无法增殖。或用 vantictumab 进行基因缺失足以抑制有或没有 突变的胃腺瘤的生长。Vantictumab 目前正在进行用于晚期胰腺癌、肺癌和乳腺癌的 Ib 期临床试验。我们的数据扩展了可能受益于这种治疗方法的患者范围，因为我们证明无论 突变状态如何，这种药物将在治疗胃癌患者方面有效。意义：Wnt 受体 Fzd7 在胃癌发生中起着至关重要的作用，与 突变状态无关，因此靶向 Wnt/Fzd7 可能对胃癌患者具有治疗益处。
