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.

前肠癌（肝细胞癌、胃癌和胰腺癌）由于诊断较晚、可行的靶向治疗方法很少以及肿瘤发育各个阶段（从化生到不典型增生再到癌）的分子谱不明确，因此具有致命性且难以治疗。最近的研究支持 TGF-B 信号传导在抑制这些肿瘤中发挥关键作用，但其作用机制及其重要的具体阶段仍不清楚。 Smad3/4 接头蛋白 ELF 是 TGF-B 肿瘤抑制功能的强大效应子。我们之前发现，ELF 的缺失会导致肝癌 (HCC) 和胃肠道 (GI) 癌的急剧自发形成，迄今为止测试的人类 HCC 和胃癌细胞系中有 11% 存在外显子 15 突变。 Elf[+/-]和elf[+/-]/Smad3[+/-]小鼠自发地出现内脏肿大和多种胃肠道癌症（70%的小鼠），包括转移性胰腺癌、HCC、肠腺癌和其他癌症。该表型提供了令人信服的证据，证明 elf[+/-] 和 elf[+/-]/Smad3[+/-] 小鼠是遗传性人类癌症综合征 Beckwith-Wiedemann (BWS) 的模型。这些动物的肿瘤中存在高水平的细胞周期调节因子，包括 CDK4、c-Myc、h-TERT、B-catenin 和 E3 连接酶 PRAJA。该 P01 应用的总体假设是，TGF-B 肿瘤抑制途径（通过 ELF、Smad3 和 Smad4）的破坏会导致细胞的增殖潜力，然后获得次级事件，例如包括 wnt 途径在内的途径的激活（ B-连环蛋白）、细胞周期调节因子（例如 CDK4、c-Myc、端粒酶、E3 连接酶（包括 PRAJA 等）），导致胃肠道癌症。该 PO1 建议 1) 使用在特定途径（包括 wnt、TGF-B、myc、端粒酶 (TERT)、CDK4）中具有预定突变的动物模型来确定它们在 BWS 和前肠癌形成中的作用； 2) 开发针对这些致命人类癌症的标记物和靶向治疗方法。项目 1，L. Mishra 博士利用小鼠模型系统，计划找出 TGF-β 信号传导和细胞周期蛋白 (CDK4) 以及 E3 连接酶 PRAJA 之间的串扰如何调节前肠肿瘤抑制，并确定ELF/Smads 作为功能性新标记物，用于 BWS 和人类胃肠道 (GI) 癌症的检测和治疗反应。项目 2. S. Byers 博士计划在上述小鼠模型系统中表征激活的 (B-连环蛋白/TCF) 的作用，并利用维生素 D 类似物开发人类癌症的治疗策略，该策略也将在项目 1、3 中使用4. 在项目 3 中，R. Schlegel 博士和 B. Mishra 博士计划确定 ELF 和 Smad3 在调节人类 TERT 和 c-Myc 在前肠癌中的作用， E. P. Reddy 博士将这些研究与项目 1、2 和 4 转化为人类标记物和治疗策略，旨在通过转基因模型系统确定 CDK4 在前肠癌中的作用并启动小分子的开发。用于治疗的 CDK4 抑制剂将在项目 1、2 和 3 中使用。该项目将由三个核心提供后勤支持：动物核心 (A)、细胞和组织核心(B) 和行政核心 (C)。这些核心将实现所有研究项目所必需的高效合作和成本节约。该计划项目下提出的研究应使科学界更好地了解调节前肠的机制。癌症的发展。值得注意的是，该计划有望在实验室中产生针对这些难以治疗的致命癌症的新疗法，然后将结果迅速转化为床边的临床护理。