ERBB receptors in normal and cancerous colon biology

描述（由申请人提供）：结直肠癌（CRC）是第四大最常见的诊断癌症，占西方社会癌症死亡人数的第二位。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），其是许多上皮细胞类型使用的主要促有丝分裂信号受体。支持EGFR在CRC发展中的重要性，我们和其他人已经观察到EGFR的抑制显著减弱ApcMin小鼠模型中肠和结直肠肿瘤的发展。然而，即使EGFR活性显著降低，一些肿瘤仍然出现，这意味着存在EGFR损失的补偿机制。该观察结果与人类癌症治疗特别相关，因为不存在可以基于CRC对EGFR抑制剂的可能敏感性来划分CRC的经验证的生物标志物或独特的基因表达特征。小鼠模型提供了定义可能对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补偿信号传导网络，这将成为对EGFR抑制剂治疗耐药的癌症的极好的治疗靶点。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，缺乏数据存在定义在CRC发展过程中的Erbb基因的体内功能作用或其在肿瘤发生过程中与EGFR的关系。通过利用我们开发的几种新的小鼠模型，我们处于独特的地位，可以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EGFR抑制时癌症使用的补偿网络，确定抗EGFR治疗耐药癌症中新治疗靶点的线索，并揭示CRC发展过程中Erbb基因之间的作用和功能相互作用。公共卫生相关性：生物标志物的鉴定表明哪些患者将对特定的分子靶向治疗（如针对EGFR的分子靶向治疗）有反应，这对于提高临床治疗的疗效具有高度意义。类似地，鉴定补偿靶向途径损失的途径提供了改善治疗益处的靶点。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。

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.