UCI 07-70: INHIBITING EGF RECEPTOR SIGNALING IN ABERRANT CRYPT FOCI OF THE COLON

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 结直肠癌(CRC)是美国癌症死亡的第二大原因。可悲的是，很大一部分结直肠癌是可以预防的，因为肿瘤生长相对缓慢，而且我们有能力通过结肠镜检查及早发现癌症。大多数结直肠癌病例先于先驱性腺瘤，最近美国结直肠癌发病率的下降归因于对腺瘤的筛查增加。因此，通过靶向结直肠上皮中的癌前体来预防结直肠癌已经引起了人们的浓厚兴趣。非甾体抗炎药和环氧合酶-2抑制剂已显示出预防腺瘤的活性；然而，心血管副作用造成了对它们是否适合这一适应症的不确定性。因此，需要新的代理人。在结直肠癌(CRC)、非小细胞肺癌、胰腺癌和头颈癌中，EGFR抑制具有显著的缩小肿瘤和延长生存时间的活性。虽然大部分注意力集中在EGFR抑制剂治疗晚期恶性肿瘤上，但有重要证据表明，EGFR在结直肠癌中也发挥着重要作用。 而EGFR抑制剂可阻断肿瘤的启动。在ApcMin小鼠中，EGFR失活基本上消除了腺瘤的形成。同样，用EGFR小分子抑制剂吉非替尼治疗小鼠和大鼠结直肠癌模型也可以阻止腺瘤的形成。因此，除了对其在肿瘤进展中的作用进行更深入的研究外，EGFR很可能在腺瘤的启动过程中发挥作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Colorectal cancer (CRC) is the 2nd leading cause of cancer death in the United States. Tragically, a large proportion of CRC is preventable because the tumors are relatively slow growing and we have the ability to detect cancers early with colonoscopy. Most CRC cases are preceded by precursor adenomas, and recent decreases in CRC in the US are attributable to increased screening of adenomas. There has therefore been intensive interest in preventing CRC by targeting precancerous CRC precursors in colorectal epithelium. NSAIDs and COX-2 inhibitors have shown activity in adenoma prevention; however, cardiovascular side effects have created uncertainty as to their suitability for this indication. Therefore, new agents are needed. EGFR inhibition has significant activity to shrink tumors and extend survival in colorectal cancer (CRC), non-small cell lung cancer, pancreas and head and neck cancers. While most of the focus on EGFR inhibitors has been in the treatment of advanced malignancies, there is significant evidence that EGFR also plays important roles in CRC initiation, and that EGFR inhibitors block tumor initiation. In ApcMin mice, EGFR inactivation essentially abolishes adenoma formation. Similarly, treatment of mouse and rat CRC models with the EGFR small molecule inhibitor Gefitinib also blocks adenoma formation. Therefore, it is likely that EGFR plays a role in initiation of adenomas, in addition to its more intensively studied role in tumor progression.