STUDY OF REG RECEPTOR-LIGAND BIOLOGY IN GI MUCOSA

简介(申请人提供)：结直肠癌是美国第三大常见癌症，预计2005年新增病例约为145,000例。估计的5年生存率从早期诊断(I期疾病)患者的90%到转移性结直肠癌(CRC)患者的10%不等。在这一新的应用中，我们转移到REG IV在粘膜癌发展中的作用的研究。作为这一应用的基础，当前资助期内的研究已经证明：i)Reg IV在腺瘤性息肉和癌组织中的表达增加，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APCmin/+小鼠APC基因的第二次自发突变和腺瘤组织学变化相一致；iii)Reg IV是结直肠癌中信号通路(EGFR-Akt-AP1)的有效激活子，导致Bcl-2、Bcl-xL、Survivin和基质溶素的表达增加。这些基因都与晚期CRC预后不良有关，iv)重组Reg IV蛋白治疗CRC细胞可显著降低放射或化疗药物后程序性细胞死亡(凋亡)的易感性，以及v)功能阻断抗Reg IV单抗或干扰RNA对细胞生长具有强大的拮抗作用，并增加放射或化疗药物诱导的凋亡死亡的易感性。通过利用提案中概述的方法，我们的目标是更好地了解结直肠癌对传统治疗的临床耐药性所涉及的机制，并确定REG IV作为不良预后的原因所起的作用。这些研究还将为REG IV拮抗剂的作用提供新的见解，并为开发活性于胃肠腺癌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.