ERBB receptors in normal and cancerous colon biology

描述（由申请人提供）：结直肠癌（CRC）是西方社会第四大最常诊断的癌症，占癌症死亡人数的第二大。在过去十年中出现的主要分子靶点之一是表皮生长因子受体（EGFR），这是许多上皮细胞类型使用的主要有丝分裂信号受体。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可显著减缓肠道和结直肠肿瘤的发展。然而，即使EGFR活性显著降低，一些肿瘤仍会出现，这意味着存在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存在，可以根据它们对EGFR抑制剂的可能敏感性来划分crc。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志物的潜力。同样重要的是，小鼠模型有潜力识别在EGFR活性降低的情况下利用的代偿信号网络，这将成为对EGFR抑制剂治疗耐药的癌症的极好治疗靶点。其他Egfr/ erbb相关基因也在crc中表达，推动了泛erbb抑制剂治疗的发展。然而，关于Erbb基因在结直肠癌发展过程中的体内功能作用，以及它们在肿瘤发生过程中与EGFR的关系，目前还缺乏相关数据。通过开发几种新的鼠标模型，我们有独特的优势来解决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志物，研究当EGFR被抑制时癌症使用的代偿网络，确定对抗EGFR治疗有抗性的癌症的新治疗靶点，并揭示Erbb基因在结直肠癌发展过程中的作用和功能相互作用。公共卫生相关性：识别生物标志物，表明哪些患者将对特定的分子靶向治疗（如针对EGFR的治疗）有反应，这对提高临床治疗的疗效非常重要。同样，识别弥补靶向途径损失的途径提供了改善治疗效果的靶标。本应用程序中提出的新型小鼠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.