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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 结直肠癌（CRC）是美国癌症死亡的第二大原因。不幸的是，很大一部分CRC是可以预防的，因为肿瘤生长相对缓慢，我们有能力通过结肠镜检查早期发现癌症。大多数CRC病例之前都有前体腺瘤，最近美国CRC的减少可归因于腺瘤筛查的增加。因此，通过靶向结肠直肠上皮中的癌前CRC前体来预防CRC引起了强烈的兴趣。NSAID和考克斯-2抑制剂在腺瘤预防中显示出活性;然而，心血管副作用使其是否适用于该适应症产生了不确定性。因此，需要新的代理人。EGFR抑制具有显著的缩小肿瘤和延长结肠直肠癌（CRC）、非小细胞肺癌、胰腺癌和头颈癌的存活的活性。虽然EGFR抑制剂的研究主要集中在晚期恶性肿瘤的治疗上，但有大量证据表明EGFR在结直肠癌中也起着重要作用 EGFR抑制剂阻断肿瘤起始。在ApcMin小鼠中，EGFR失活基本上消除了腺瘤形成。类似地，用EGFR小分子抑制剂吉非替尼治疗小鼠和大鼠CRC模型也阻断腺瘤形成。因此，EGFR除了在肿瘤进展中更深入研究的作用外，很可能在腺瘤的起始中起作用。

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.