STUDY OF REG RECEPTOR-LIGAND BIOLOGY IN GI MUCOSA

描述（由申请人提供）：结直肠癌是美国第三大常见癌症，预计2005年约有145，000例新发病例。早期诊断（I期疾病）患者的估计5年生存率为90%，转移性结直肠癌（CRC）患者的5年生存率降至<10%。在这个更新申请中，我们转向研究Reg IV在粘膜癌发展中的作用。在本资助期间进行的研究，作为本申请的基础，已经证明：i）Reg IV的表达在腺瘤性息肉和CRC中增加，通常达到非常高的水平，ii）Reg IV的表达增加是肿瘤形成的最早步骤之一，与APC基因的第二次自发突变和APC min/+小鼠中的组织学腺瘤变化一致，iii）Reg IV是CRC中信号传导途径（EGFR-Akt-AP 1）的有效激活剂，并导致Bcl-2、Bcl-XL、存活素和基质溶解素的表达增加。这些基因以前都与晚期CRC的不良预后相关。iv）用重组Reg IV蛋白治疗CRC细胞显著降低了它们对通过程序性细胞死亡导致的死亡的易感性。（细胞凋亡），在放射或化疗药物之后，和v）功能阻断抗-Reg IV mAb或干扰RNA对细胞生长具有有效的拮抗作用，并增加对辐射后细胞凋亡的易感性，或化疗药物的施用。通过利用提案中概述的方法，我们的目标是更好地了解CRC对常规治疗的临床耐药机制，并确定Reg IV作为不良结局原因的作用。这些研究还将为Reg IV拮抗剂的作用提供新的见解，并为开发在胃肠道腺癌中具有活性的治疗试剂奠定基础。

DESCRIPTION (provided by applicant): Colorectal cancer is the third most common cancer in the US, with approximately 145,000 new cases expected in 2005. Estimated 5-year survival rates range from 90% for patients with early diagnosis (stage I disease) and fall to <10% for patients with metastatic colorectal cancer (CRC). In this renewal application, we move to studies of the role of Reg IV in the development of mucosal cancers. Studies during the current funding period, presented as the foundation for this application, have demonstrated that: i) Expression of Reg IV is increased in adenomatous polyps and in CRCs, often to very high levels, ii) Increased expression Reg IV is one of the earliest steps in the formation of tumors, coinciding with the second spontaneous mutation in the APC gene and adenomatous change by histology in APCmin/+mice, iii) Reg IV is a potent activator of a signaling pathway (the EGFR-Akt-AP1) in CRC and leads to increased expression of Bcl-2, Bcl-XL, survivin and matrilysin. These genes have all previously been associated with a poor prognosis in advanced CRC, iv) Treatment of CRC cells with recombinant Reg IV protein significantly reduces their susceptibility to death by programed cell death (apoptosis), following radiation or chemotherapeutic drugs, and v) Function blocking anti-Reg IV mAbs or interfering RNAs have potent antagonistic effects on cell growth and increase susceptibility to apoptotic death following radiation or administration of chemotherapeutic drugs. By utilizing the approaches, outlined in the proposal, our goal is to better understand the mechanisms involved in the clinical resistance of CRC to conventional therapy and to ascertain the role of Reg IV as a cause of poor outcome. These studies will also provide new insight into the role of Reg IV antagonists and lay the groundwork for development of therapeutic reagents active in gastrointestinal adenocarcinomas.