CELLULAR AND MOLECULAR MECHANISMS OF GASTROINTESTINAL CANCERS

胃肠癌的细胞和分子机制

• 批准号: 8329637
• 负责人: Lopa Mishra
• 金额: $ 131.04万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-10 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8329637
• 关键词: Adaptor Signaling Protein; Adenocarcinoma; Animal Model; Animals; Beckwith-Wiedemann Syndrome; Biological Models; CDK4 gene; Cancer cell line; Carcinoma; Cell Cycle; Cell Cycle Proteins; Cells; Communities; Cost Savings; Cyclin-Dependent Kinase Inhibitor 2A; Detection; Development; Diagnosis; Dysplasia; Event; Exons; Human; Inherited; Intestines; Liver; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Metaplasia; Modeling; Molecular; Molecular Profiling; Mus; Mutation; Pancreas; Pathway interactions; Phenotype; Primitive foregut structure; Research Project Grants; Role; Signal Transduction; Staging; Stomach; Telomerase; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; Transgenic Model; Translating; Tumor Suppression; Tumor Suppressor Proteins; Visceromegaly; Vitamin D Analog; c-myc Genes; clinical care; malignant stomach neoplasm; mouse model; novel marker; programs; small molecule; therapeutic target; treatment response; treatment strategy; tumor; ubiquitin-protein ligase

Cancers of the foregut (hepatocellular, gastric and pancreatic) are lethal and difficult to treat due to late diagnosis, few viable targeted therapeutics and unclear molecular profiling of each stage of tumon development, from metaplasia to dysplasia to carcinoma. Recent studies support a key role for TGF-B signaling in suppressing these tumors, yet its mechanism of action and the specific stages at which it is important remain unclear. The Smad3/4 adaptor protein ELF is a powerful effector of TGF-B tumor suppressor function. We previously found that deletion of ELF results in a dramatic and spontaneous formation of liver (HCC) and gastrointestinal (GI) cancers, with exon 15 mutations in 11% of human HCC and gastric cancer cell lines tested so far. Elf[+/-] and elf[+/-]/Smad3[+/-] mice develop visceromegaly and multiple Gl cancers (70% of mice), including metastatic pancreatic, HCC, intestinal adenocarcinomas and others spontaneously. This phenotype provides compelling evidence that elf[+/-] and elf[+/-]/Smad3[+/-] mice are a model of the hereditary human cancer syndrome, Beckwith-Wiedemann (BWS). High levels of cell cycle regulators including CDK4, c-Myc, h-TERT, B-catenin, and the E3 ligase PRAJA occur in tumors in these animals. The overall hypothesis of this P01 application, is that disruption of the TGF-B tumor suppressor pathway (through ELF, Smad3 and Smad4) leads to a proliferative potential in cells that then acquire secondary events such as activation of pathways that include the wnt pathway (B-catenin), cell cycle regulators such as CDK4, c-Myc, telomerase, E3 ligases that include PRAJA and others, resulting in gastrointestinal cancers. This PO1 proposes to 1) Use animal models that have predetermined mutations in specific pathways that include wnt, TGF-B, myc, telomerase (TERT), CDK4 to determine their role in BWS and foregut cancer formation; 2) Develop markers and targeted therapeutics to these lethal human cancers. Project 1, Dr. L. Mishra, utilizing a mouse model system, plans to find out how cross talk between TGF-beta signaling and cell cycle proteins (CDK4) and the E3 ligase PRAJA modulate foregut tumor suppression and to determine the potential role of ELF/Smads as functional new markers for the detection and treatment response of BWS and human gastrointestinal (GI) cancers. Project 2. Dr. S. Byers plans to characterize the role of activated (B-catenin/TCF in the mouse model systems above, and develop a therapeutics strategy to human cancers with Vitamin D analogs which will also be utilized in Project 1, 3 and 4. In Project 3, Drs. R. Schlegel and B. Mishra, plan to determine the role of ELF and Smad3 in modulation of human TERT and c- Myc in cancers of the foregut, and translate these studies with Projects 1, 2 and 4 in terms of human markers and treatment strategies. Project 4 by Dr. E. P. Reddy, aims to determine the role of CDK4 in foregut cancers with transgenic model systems and initiate the development of small-molecule CDK inhibitors of CDK4 for therapy that will be utilized in Projects 1, 2 and 3. The program will be logistically supported by three cores: an Animal Core (A), a Cell and Tissue Core (B), and an Administrative Core (C). The cores will enable efficient cooperation and cost savings essential for all the research projects. The studies proposed under this Program Project should provide the scientific community with a better understanding of the mechanisms that regulate foregut cancer development. Significantly, this program promises to yield new therapies targeted at these difficult-to-treat lethal cancers at the bench, and then to translate the results rapidly into clinical care, at the bedside.

由于晚期诊断，几乎没有可行的靶向疗法以及不明确的肿瘤发育阶段的不明确的分子分析，从化合物到增生到增生性肿瘤到癌瘤，肝细胞，胃和胰腺的癌症（肝细胞，胃和胰腺）是致命的，难以治疗。最近的研究支持TGF-B信号在抑制这些肿瘤中的关键作用，但其作用机理和重要的特定阶段尚不清楚。 SMAD3/4适配器蛋白ELF是TGF-B肿瘤抑制器功能的强大效应器。我们先前发现，精灵的缺失会导致肝（HCC）和胃肠道（GI）癌症的戏剧性和自发形成，到目前为止，人类HCC和胃癌细胞系中有11％的外显子15突变。 ELF [+/-]和ELF [+/-]/SMAD3 [+/-]小鼠会出现内脏肿大和多种GL癌（70％的小鼠），包括转移性胰腺，HCC，HCC，肠道腺癌和其他人。该表型提供了令人信服的证据，表明Elf [+/-]和Elf [+/-]/SMAD3 [+/-]小鼠是遗传性人类癌综合征，Beckwith-Wiedemann（BWS）的模型。高水平的细胞周期调节剂，包括CDK4，C-MYC，H-TERT，B-catenin和E3连接酶Praja，都发生在这些动物的肿瘤中。 The overall hypothesis of this P01 application, is that disruption of the TGF-B tumor suppressor pathway (through ELF, Smad3 and Smad4) leads to a proliferative potential in cells that then acquire secondary events such as activation of pathways that include the wnt pathway (B-catenin), cell cycle regulators such as CDK4, c-Myc, telomerase, E3 ligases that include PRAJA and others,导致胃肠道癌。该PO1提议1）使用在包括Wnt，TGF-B，MYC，TERMERASE（TERT），CDK4在内的特定途径中具有预定突变的动物模型来确定其在BWS和Foregut Cancer形成中的作用； 2）为这些致命的人类癌症开发标记和靶向疗法。 L. Mishra博士利用鼠标模型系统，计划找出TGF-beta信号传导和细胞周期蛋白（CDK4）和E3连接酶Praja调制的前体肿瘤抑制的方式，并确定ELF/SMAD的潜在作用，并将ELF/SMAD作为检测和治疗响应的功能性响应（GI）和人类的效果（GI）的效果（GI）的潜在作用。项目2。S.Byers博士计划表征激活的作用（B-catenin/tcf在上面的鼠标模型系统中，并为人类癌症制定了一种治疗策略，该策略还将在项目1、3和4中使用，在项目3中也将在项目3中使用。 Foregut，并通过E. P. Reddy博士的项目1、2和4转化这些研究。细胞和组织核心（B）和行政核心（C）将使所有研究项目中提出的研究能够有效地合作和成本节省。值得注意的是，该计划有望在板凳上产生针对这些难以治疗的致命癌症的新疗法，然后在床边迅速转化为临床护理。