ERBB receptors in normal and cancerous colon biology

正常和癌性结肠生物学中的 ERBB 受体

• 批准号: 8016074
• 负责人: DAVID W. THREADGILL
• 金额: $ 27.8万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8016074
• 关键词: Ablation; Accounting; Address; Alleles; Attenuated; Automobile Driving; Biological Markers; Biology; Cancerous; Cessation of life; Clinical Treatment; Colon; Colorectal Cancer; Colorectal Neoplasms; Data; Development; Dose; EGFR gene; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epithelial Cells; Evaluation; Funding; Gene Expression; Gene Expression Profile; Genes; Glean; Grant; Hand; Health; Human; Intestinal Neoplasms; Ligands; Malignant Neoplasms; Modeling; Molecular Target; Mus; Pathway interactions; Patients; Positioning Attribute; Principal Investigator; Publications; Publishing; Reagent; Receptor Inhibition; Receptor Signaling; Resistance; Role; Signal Transduction; Societies; Therapeutic; Work; base; cancer diagnosis; cancer therapy; cell type; erbB Genes; improved; in vivo; inhibitor/antagonist; insight; mouse model; new therapeutic target; novel; programs; receptor; therapeutic target; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and accounts for the second largest number of cancer deaths in Western societies. One of the major molecular targets to arrise over the last decade is the epidermal growth factor receptor (EGFR), a major mitogenic signal receptor used by many epithelial cell types. Supporting the importance of EGFR in CRC development, we and others have observed that inhibition of EGFR dramatically attenuates development of intestinal and colorectal tumors in the ApcMin mouse model. Yet, some tumors still arise, even with significant reductions in EGFR activity, implying the existence of compensatory mechanisms for the loss of EGFR. This observation is particularly relevant to human cancer therapy since no validated biomarkers or unique gene expression signatures exist that can partition CRCs based upon their likely sensitivity to EGFR inhibitors. Mouse models offer the potential to define the context and biomarkers for tumors likely to respond to EGFR inhibitor therapy. Equally importantly, mouse models have the potential to identify compensatory signaling networks utilized in the context of reduced EGFR activity, which will make excellent therapeutic targets for cancers resistant to EGFR inhibitor therapy. Other Egfr/Erbb-related genes are also expressed in CRCs, driving the development of pan-ERBB inhibitor therapies. However, scant data exists defining the in vivo functional role of Erbb genes during CRC development or their relationship to EGFR during tumorigenesis. We are uniquely positioned to address many of these open questions by exploiting several new mouse models we developed. These models are ideally suited to develop a gene expression biomarker for sensitivity to EGFR inhibition, to investigate the compensatory networks used by cancers when EGFR is inhibited, identifying leads for new therapeutic targets in cancers resistant to anti-EGFR therapy, and to expose the role and functional interactions among the Erbb genes during CRC development. PUBLIC HEALTH RELEVANCE: The identification of biomarkers that indicate which patients will respond to specific molecular-targeted therapies like those against EGFR is highly significant and relevant to improving the efficacy of clinical treatments. Similarly, the identification of pathways that compensate for the loss of targeted pathways offers in targets to improve therapeutic benefit. The use of novel mouse models as proposed in this application has the potential to provide these insights.

描述（由申请人提供）：结直肠癌 (CRC) 是第四大最常诊断的癌症，占西方社会第二大癌症死亡人数。过去十年出现的主要分子靶标之一是表皮生长因子受体（EGFR），它是许多上皮细胞类型使用的主要有丝分裂信号受体。我们和其他人观察到，在 ApcMin 小鼠模型中，抑制 EGFR 可显着减弱肠道和结直肠肿瘤的发展，这支持了 EGFR 在 CRC 发展中的重要性。然而，即使 EGFR 活性显着降低，一些肿瘤仍然会出现，这意味着存在针对 EGFR 损失的补偿机制。这一观察结果与人类癌症治疗特别相关，因为没有经过验证的生物标志物或独特的基因表达特征可以根据 CRC 可能对 EGFR 抑制剂的敏感性来划分 CRC。小鼠模型有可能定义可能对 EGFR 抑制剂治疗产生反应的肿瘤的背景和生物标志物。同样重要的是，小鼠模型有潜力识别在 EGFR 活性降低的情况下使用的补偿信号网络，这将为对 EGFR 抑制剂治疗耐药的癌症提供极好的治疗靶点。其他 Egfr/Erbb 相关基因也在 CRC 中表达，推动了泛 ERBB 抑制剂疗法的发展。然而，缺乏数据来定义 Erbb 基因在 CRC 发展过程中的体内功能作用或它们在肿瘤发生过程中与 EGFR 的关系。我们拥有独特的优势，可以通过利用我们开发的几种新小鼠模型来解决许多这些悬而未决的问题。这些模型非常适合开发对 EGFR 抑制敏感的基因表达生物标志物，研究当 EGFR 被抑制时癌症使用的补偿网络，识别抗 EGFR 治疗耐药的癌症中新治疗靶点的线索，并揭示 Erbb 基因在 CRC 发展过程中的作用和功能相互作用。公共卫生相关性：识别表明哪些患者将对特定分子靶向疗法（如针对 EGFR 的疗法）产生反应的生物标志物非常重要，并且与提高临床治疗的疗效相关。类似地，补偿靶向途径损失的途径的鉴定提供了提高治疗效果的靶点。本申请中提出的新型小鼠模型的使用有可能提供这些见解。