MICA: Targeting the Wnt Receptor Frizzled-7 for the Treatment of Gastric Cancer

胃癌是第三大常见的癌症死亡原因，每年约有70万人确诊，在全球范围内占相当大的发病率和死亡率。与肠道或乳房等其他器官相比，在正常情况下(体内平衡)和癌症期间调节胃的细胞和分子事件知之甚少。这反映在可用于治疗胃癌的相对较少的靶向治疗上，并突显了通过深入了解调节胃肿瘤起始、生长和进展的细胞信号来确定这种疾病的新治疗靶点的迫切需要。细胞信号在调节细胞决策中发挥着关键作用，包括细胞是否分裂、分化为特定的细胞类型、迁移或死亡。这些细胞命运在胚胎发育期间和生命早期受到严格控制，以确保细胞生长，并分化为成人身体许多不同组织类型所需的所有细胞类型。在成年人中，细胞信号控制着组织的动态平衡，因此，当这种信号变得不受调控时，它可以重新激活信号来触发细胞生长，从而将正常细胞转变为癌细胞，后者可以不受调控地分裂为肿瘤。我和其他人已经证明了这一点的途径之一是Wnt信号途径。这一途径是胚胎正常发育所必需的，也是包括肠道和胃在内的几个器官中干细胞功能的关键。虽然我们对从细胞表面到激活Wnt途径靶基因表达的信号转导有很好的了解，但对10种不同的FrizzledWnt受体中的哪一种传递这一信号知之甚少。事实上，我们最近首次证明了FZD7是主要的Wnt受体，通过传递关键的Wnt信号来调节肠道和胃中的干细胞功能。该项目的拨款申请将决定抑制FZD7治疗胃癌的疗效。我已经产生了一系列强有力的初步数据，表明在两种胃癌小鼠模型中FZD7的基因缺失能够阻断胃癌的生长。这项应用旨在通过首先研究FZD7的缺失是否也可以阻止大型已建立的胃肿瘤的生长来建立这些令人兴奋的结果。然后我们将使用一种名为shRNA的技术，在这种技术中，我们可以打开或关闭FZD7的表达。这将使我们能够确定一旦FZD7水平首先降低，然后恢复到正常水平，胃肿瘤生长会发生什么。这些实验将在人类胃癌细胞中进行，并使用针对包括FZD7在内的Wnt受体的日落的封闭抗体进行额外的实验。这种抗体已经在对肺癌、乳腺癌和胰腺癌等其他癌症进行临床试验，因此该项目的结果将直接为使用这种FZD抗体治疗胃癌的新的潜在临床试验提供信息。该项目的最终目标将是全面研究胃癌细胞如何对FZD7的抑制做出反应，即使在被认为在受体下游水平激活Wnt通路的胃癌细胞中也是如此。这不仅将为Wnt受体如何调控胃癌细胞的机制提供新的见解，还将有助于选择哪些患者将最适合这种治疗方法。

Gastric cancer is the third most common cause of death due to cancer, with approximately 700,000 cases diagnosed annually, and accounts for substantial morbidity and mortality worldwide. Compared to other organs such as the intestine or breast, the cellular and molecular events that regulate the stomach during normal conditions (homeostasis) and cancer are poorly understood. This is reflected in the relatively few targeted therapies available to treat gastric cancer, and highlights an urgent need to identify new therapeutic targets for this disease, by gaining insight into the cell signaling that regulates gastric tumour initiation, growth and progression.Cell signaling plays critical roles in regulating cellular decisions including whether a cell divides, differentiates into a specialized cell type, migrates, or dies. These cellular fates are tightly controlled during development of the embryo and during early life to ensure that cells grow, and differentiate into all the cell types required for the many different tissue types of the adult body. In adults cell signaling controls the homeostasis of tissues, and consequently when this signaling becomes deregulated it can re-activate the cues to trigger cell growth and thus transform a normal cell into a cancer cell which can divide unregulated into a tumour. One of the pathways in which this has been demonstrated by myself and others is the Wnt signaling pathway. This pathway is required for the normal development of embryos, and is also critical for the function of stem cells in several organs including the intestine and the stomach. Although we have a good knowledge of the signal transduction from the cell surface through to activating the expression of target genes for the Wnt pathway, very little is known about which of the ten different Frizzled (Fzd), Wnt receptors transmit this signal. Indeed, we were the first to demonstrate recently that Fzd7 is the predominant Wnt receptor transmitting critical Wnt signals to regulate stem cell function in the intestine and the stomach.This project grant application will determine the therapeutic benefit of inhibiting Fzd7 for the treatment of gastric cancer. I have generated a body of strong preliminary data which shows that genetic deletion of Fzd7 in two mouse model of gastric cancer is able to block the growth of gastric tumors. This application aims to build on these exciting results by first investigating if deletion of Fzd7 can also block the growth of large, established gastric tumors. Then we shall employ a technology called shRNA in which we can switch on or off the expression of Fzd7. This will enable us to determine what happens to gastric tumor growth once the levels of Fzd7 are first reduced and then returned to normal levels. These experiments will be performed in human gastric cancer cells and complimented with additional experiments using a blocking antibody targeting a sunset of Wnt receptors including Fzd7. This antibody is already in clinical trials for other cancers including lung, breast and pancreas, and thus the results of this project will directly inform new potential clinical trials using this Fzd antibody to treat gastric cancer.The final aim of this project will be a comprehensive study into how gastric cancer cells can respond to inhibition of Fzd7 even in gastric cancer cells which are thought to activate the Wnt pathway at a level downstream of the receptor. This will not only provide new insight into the mechanism of how Wnt receptors can regulate gastric cancer cells, but will also help select which patients will be most suitable to this therapeutic approach.