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: 8213608
• 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 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8213608
• 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。这一观察结果与人类癌症治疗特别相关，因为不存在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对EGFR抑制剂的可能敏感性对其进行分区。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）产生反应，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。

项目成果

Efficacy of EGFR inhibition is modulated by model, sex, genetic background and diet: implications for preclinical cancer prevention and therapy trials.

EGFR 抑制的功效受模型、性别、遗传背景和饮食的调节：对临床前癌症预防和治疗试验的影响。

• DOI: 10.1371/journal.pone.0039552
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Rinella,EricaS;Threadgill,DavidW
• 通讯作者: Threadgill,DavidW

Epithelial-specific ERBB3 deletion results in a genetic background-dependent increase in intestinal and colon polyps that is mediated by EGFR.

• DOI: 10.1371/journal.pgen.1009931
• 发表时间: 2021-11
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Mantilla Rojas C;McGill MP;Salvador AC;Bautz D;Threadgill DW
• 通讯作者: Threadgill DW

Epidermal ADAM17 maintains the skin barrier by regulating EGFR ligand-dependent terminal keratinocyte differentiation.

• DOI: 10.1084/jem.20112258
• 发表时间: 2012-06-04
• 期刊: The Journal of experimental medicine
• 作者: Franzke CW;Cobzaru C;Triantafyllopoulou A;Löffek S;Horiuchi K;Threadgill DW;Kurz T;van Rooijen N;Bruckner-Tuderman L;Blobel CP
• 通讯作者: Blobel CP

Generation and validation of mice carrying a conditional allele of the epidermal growth factor receptor.

• DOI: 10.1002/dvg.20464
• 发表时间: 2009-03
• 期刊: GENESIS
• 影响因子: 1.5
• 作者: Lee, Tang-Cheng;Threadgill, David W.
• 通讯作者: Threadgill, David W.

Wildtype epidermal growth factor receptor (Egfr) is not required for daily locomotor or masking behavior in mice.

小鼠的日常运动或掩蔽行为不需要野生型表皮生长因子受体 (Egfr)。

• DOI: 10.1186/1740-3391-4-15
• 发表时间: 2006
• 期刊: Journal of circadian rhythms
• 作者: Roberts,ReadeB;Thompson,CarolL;Lee,Daekee;Mankinen,RichardW;Sancar,Aziz;Threadgill,DavidW
• 通讯作者: Threadgill,DavidW