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

MICA：靶向 Wnt 受体 Frizzled-7 治疗胃癌

• 批准号: MR/R026424/1
• 负责人: Toby Phesse
• 金额: $ 80.46万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR026424%2F1
• 关键词: MICA; Targeting; Wnt; Receptor; Frizzled

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.

胃癌是癌症引起的第三大死亡原因，每年约有70万例病例，并且在全球范围内占据了大量发病率和死亡率。与其他器官（例如肠子或乳房）相比，在正常情况下（稳态）和癌症调节胃的细胞和分子事件知之甚少。这反映在相对较少的针对治疗胃癌的靶向疗法中，并突出了迫切需要通过深入了解调节细胞信号传导的细胞信号传导，从而在调节包括细胞的细胞群体中，分别分配了分类，从而在调节细胞决策中起着重要的作用。这些细胞命运在胚胎的发育过程中以及在早期生命的过程中受到严格控制，以确保细胞生长，并分化为许多不同组织类型所需的所有细胞类型。在成年人中，细胞信号控制组织的稳态，因此，当该信号传导受管制时，它可以重新激活线索以触发细胞生长，从而将正常细胞转化为可以将不管制成肿瘤分为肿瘤的癌细胞。我和他人证明这一点的途径之一是Wnt信号通路。该途径是胚胎正常发育所必需的，对于包括肠和胃在内的多个器官中的干细胞功能也至关重要。尽管我们对从细胞表面到激活Wnt途径的靶基因的表达的信号转导有很好的了解，但对于十种不同的卷曲（FZD）中的哪一个知之甚少，Wnt受体会传递该信号。的确，我们最近第一个证明FZD7是传输关键Wnt信号以调节肠和胃中干细胞功能的主要Wnt受体。此项目赠款的应用将确定抑制FZD7治疗胃癌的治疗益处。我已经产生了一系列强大的初步数据，这表明在两种小鼠胃癌模型中FZD7的遗传缺失能够阻止胃肿瘤的生长。该应用程序旨在通过首先研究FZD7的缺失是否也可以阻止大型胃肿瘤的生长，以基于这些令人兴奋的结果。然后，我们将采用一种称为shRNA的技术，在该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的水平降低，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受体日落的封闭抗体进行了其他实验。 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.这不仅将提供有关Wnt受体如何调节胃癌细胞的机制的新见解，而且还将帮助选择哪些患者最适合这种治疗方法。

项目成果

Wnt Signalling in Gastrointestinal Epithelial Stem Cells.

• DOI: 10.3390/genes9040178
• 发表时间: 2018-03-23
• 期刊: Genes
• 影响因子: 3.5
• 作者: Flanagan DJ;Austin CR;Vincan E;Phesse TJ
• 通讯作者: Phesse TJ

IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization

• DOI: 10.1038/s41467-019-10676-1
• 发表时间: 2019-06-21
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Eissmann, Moritz F.;Dijkstra, Christine;Ernst, Matthias
• 通讯作者: Ernst, Matthias

Development of a low seroprevalence, avß6 integrin 1 selective virotherapy based on human adenovirus type 10.

开发基于人类 10 型腺病毒的低血清流行率 avä6 整合素 1 选择性病毒疗法。

• 发表时间: 2022
• 期刊: Oncolytics.
• 作者: Bates, E. A.

Lect2 deficiency is characterised by altered cytokine levels and promotion of intestinal tumourigenesis.

• DOI: 10.18632/oncotarget.26335
• 发表时间: 2018-11-23
• 期刊: Oncotarget
• 作者: Greenow, Kirsty R;Zverev, Matthew;Parry, Lee
• 通讯作者: Parry, Lee

The Function of Lgr5+ Cells in the Gastric Antrum Does Not Require Fzd7 or Myc In Vivo.

体内胃窦 Lgr5 细胞的功能不需要 Fzd7 或 Myc。

• DOI: 10.3390/biomedicines7030050
• 发表时间: 2019
• 期刊: Biomedicines
• 影响因子: 4.7
• 作者: Flanagan D