ERBB receptors in normal and cancerous colon biology

描述(申请人提供)：结直肠癌(CRC)是西方社会第四种最常见的癌症，也是导致癌症死亡人数第二多的疾病。在过去的十年中出现的主要分子靶点之一是表皮生长因子受体(EGFR)，它是一种主要的促有丝分裂信号受体，被许多类型的上皮细胞使用。支持EGFR在结直肠癌发展中的重要性，我们和其他人观察到，在ApcMin小鼠模型中，抑制EGFR可以显著减弱肠道和结直肠肿瘤的发展。然而，一些肿瘤仍然出现，即使EGFR活性显著降低，这意味着EGFR丢失的代偿机制存在。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记物或独特的基因表达特征可以根据癌细胞对EGFR抑制剂的可能敏感性来划分癌细胞。小鼠模型提供了确定可能对EGFR抑制剂治疗有反应的肿瘤的背景和生物标记物的可能性。同样重要的是，小鼠模型有可能识别在EGFR活性降低的背景下利用的代偿信号网络，这将成为抗药性EGFR抑制剂治疗的癌症的极佳治疗靶点。其他EGFR/ErbB相关基因也在癌组织中表达，推动了泛ERBB抑制剂治疗的发展。然而，目前还缺乏明确ErbB基因在结直肠癌发生过程中的体内功能作用或它们在肿瘤发生过程中与EGFR的关系的数据。通过利用我们开发的几个新鼠标型号，我们处于独特的地位来解决许多这些悬而未决的问题。这些模型非常适合于开发对EGFR抑制敏感的基因表达生物标记物，研究当EGFR被抑制时癌症所使用的代偿网络，确定耐药癌症的新治疗靶点的线索，以及揭示ErbB基因在结直肠癌发生过程中的作用和功能相互作用。公共卫生相关性：识别生物标记物，表明哪些患者将对特定的分子靶向治疗(如针对EGFR的治疗)产生反应，这对提高临床治疗的有效性具有非常重要的意义。同样，识别补偿靶向通路损失的通路可提供靶向，以提高治疗效益。本申请中提出的新型鼠标模型的使用有可能提供这些见解。

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.