Implications of Blockade of EGFR Axis & Src in Colorectal Cancer

该项目的目标是翻译我们对EGF受体激活的理解的最新进展 （EGFR）用于改善结直肠癌（CRC）患者的治疗。两个互补战略 将采用：抑制EGFR激活的近端事件（EGFR“轴”）和联合抑制 EGFR和Src。我们和其他人已经生成了临床前数据，并支持这样一种概念，即人们可以 联合收割机阻断EGFR -细胞表面配体切割活化中的离散步骤， 受体和受体酪氨酸激酶活性-以实现CRC中的协同生长抑制。相位 联合西妥昔单抗和厄洛替尼（特罗凯）的1/11试验已获得癌症治疗评估的批准 计划（CTEP），并将评估该策略的生物学和临床效果。我们感到鼓舞 Baselga及其同事最近提供的初步数据， 西妥昔单抗和吉非替尼在CRC患者中显示出显著的临床活性。第二种方法 将在实验室和临床研究的是抑制EGFR和Src。Src是一个有吸引力的 因为Src活性在80-90%的结直肠肿瘤中增加。我们提出了遗传和 药理学证据表明，EGFR和Src活性的联合抑制导致协同减少 肠道肿瘤负荷和生长。 项目1的具体目标是 目的1：评价抑制EGFR轴治疗晚期结直肠癌的临床和生物学效果; 目的2：评估在新辅助试验中抑制EGFR和Src的临床和生物学效应， 手术切除前有肝脏局限性转移的CRC患者; 目的3：探索新的成像模式，在小鼠中，将评估肿瘤体积，DNA复制， 细胞凋亡、血管生成和EGFR状态。其中最有前途的 在本供资周期内，成像模式将被推进到人类应用， 这些研究将通过利用1）整体磷酸（ω）-酪氨酸指纹图谱;和2）小鼠来增强，其中 人EGFR已被敲入小鼠EGFR基因座。这些研究的结果将用于 改善CRC患者的诊断和治疗，并可能适用于其他实体瘤， 依赖EGFR和Src信号。

The goal of this project is to translate recent advances in our understanding of activation of the EGF receptor (EGFR) into improved therapies for patients with colorectal cancer (CRC). Two complementary strategies will be employed: inhibition of the proximal events of EGFR activation (EGFR "axis") and combined inhibition of EGFR and Src. We and others have generated preclinical data and championed the notion that one can combine blockade of discrete steps in the activation of EGFR - cell surface ligand cleavage, ligand uptake by the receptor and receptor tyrosine kinase activity - to achieve cooperative growth inhibition in CRC. A Phase l/ll trial combining cetuximab and erlotinib (Tarceva") has been approved by the Cancer Therapy Evaluation Program (CTEP) and will evaluate the biological and clinical effect of this strategy. We are encouraged by preliminary data recently presented by Baselga and co-workers in which combined EGFR inhibition with cetuximab and gefitinib demonstrated significant clinical activity in patients with CRC. The second approach that will be studied in both the laboratory and clinic will be to inhibit both EGFR and Src. Src is an attractive target in CRC since Src activity is increased in 80-90% of colorectal tumors. We present genetic and pharmacological evidence that combined inhibition of EGFR and Src activity results in cooperative reduction in intestinal tumor burden and growth. The Specific Aims of Project 1are Aim 1: To evaluate the clinical and biological effects of inhibiting the EGFR axis in advanced CRC; Aim 2: To evaluate the clinical and biological effects of inhibiting EGFR and Src in a neoadjuvant trial of CRC patients with liver-limited metastasis prior to surgical resection; Aim 3: To explore novel imaging modalities in the mouse that will assess tumor volume, DNA replication, apoptosis, angiogenesis and EGFR status in a non-invasive manner. The most promising of these imaging modalities will be advanced to human application during the course of this funding cycle, These studies will be enhanced by utilizing 1) global phospho (<j))-tyrosine fingerprinting; and 2) mice in which human EGFR has been knocked into the mouse EGFR locus. Results from these studies will be used to improve the diagnosis and treatment of patients with CRC and may be applicable to other solid tumors that rely on EGFR and Src signaling.