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.

胃癌是第三大最常见的癌症死亡原因，每年诊断出约 700,000 例胃癌，在全世界范围内造成很高的发病率和死亡率。与肠或乳房等其他器官相比，人们对正常条件（稳态）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靶向疗法相对较少，并强调迫切需要通过深入了解调节胃肿瘤发生、生长和进展的细胞信号传导来确定该疾病的新治疗靶点。细胞信号传导至关重要在调节细胞决策中的作用，包括细胞是否分裂、分化成特殊的细胞类型、迁移或死亡。这些细胞命运在胚胎发育和早期生命过程中受到严格控制，以确保细胞生长并分化成成人身体许多不同组织类型所需的所有细胞类型。在成人中，细胞信号传导控制着组织的稳态，因此，当这种信号传导失调时，它可以重新激活触发细胞生长的信号，从而将正常细胞转化为癌细胞，癌细胞可以不受调节地分裂成肿瘤。我和其他人已经证明这一点的途径之一是 Wnt 信号传导途径。该途径是胚胎正常发育所必需的，并且对于包括肠和胃在内的多个器官中的干细胞的功能也至关重要。尽管我们对从细胞表面到激活 Wnt 途径靶基因表达的信号转导非常了解，但对于 10 种不同的卷曲 (Fzd)、Wnt 受体中哪一种传递此信号知之甚少。事实上，我们最近第一个证明 Fzd7 是主要的 Wnt 受体，传递关键的 Wnt 信号以调节肠和胃中的干细胞功能。该项目拨款申请将确定抑制 Fzd7 对治疗胃癌的治疗效果。我已经生成了大量强有力的初步数据，表明在两种胃癌小鼠模型中基因删除 Fzd7 能够阻止胃肿瘤的生长。本申请的目的是在这些令人兴奋的结果的基础上，首先研究 Fzd7 的缺失是否也可以阻止大的、已形成的胃肿瘤的生长。然后我们将采用一种称为 shRNA 的技术，通过该技术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。这些实验将在人胃癌细胞中进行，并与使用针对包括 Fzd7 在内的 Wnt 受体日落的阻断抗体的其他实验相辅相成。该抗体已经进入包括肺癌、乳腺癌和胰腺癌在内的其他癌症的临床试验，因此该项目的结果将直接为使用该 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，即使在胃癌细胞中也被认为在受体下游水平激活 Wnt 通路。这不仅将为Wnt受体如何调节胃癌细胞的机制提供新的见解，而且还将有助于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