Validation of HMGI-C as a Drug Target in Colon Cancer

描述(申请人提供)：结肠癌是美国的一个主要健康问题，1999年估计有129,400例新病例报告。结肠癌现在是美国男性和女性的第二大癌症杀手，仅次于肺癌。这种疾病的成功治疗将需要发现安全有效的药理制剂。本提案的目的是验证HMGI-C(高迁移率组I-C)作为治疗结肠癌的药物靶点。HMGI-C是一种在肿瘤发生过程中调节基因表达的结构性转录因子。 实验方法将涉及灭活Min小鼠的HMGI-C，这是一种被广泛接受的结肠癌模型，由乙基亚硝脲(ENU)诱导的小鼠APC(腺瘤性息肉病结肠)基因850密码子的无义突变引起。人类APC基因的胚系突变是导致家族性腺瘤性息肉病的原因，这是一种遗传性结肠癌。APC基因缺陷在散发性结肠肿瘤中也很常见。人们希望，HMGI-C的失活将通过抑制肿瘤的形成或进展来减轻结肠癌，从而验证HMGI-C作为结肠癌药物靶点的有效性，并为可能的药物发现进行第二阶段研究奠定基础。 建议的商业应用： 这个项目的成功完成将为发现有效的、具有临床价值的治疗结肠癌的药物开辟新的前景，这将具有巨大的商业潜力。据估计，仅在美国就报告了129,400例新的结肠癌病例，这表明对安全、可靠的药物的需求。

DESCRIPTION (provided by applicant): Colon cancer is a major health concern of the United States, with an estimated 129,400 new cases reported in 1999. Colon cancer is now the second leading cancer killer of both men and women in the U.S. after lung cancer. The successful management of this disease will require the discovery of safe and effective pharmacological agents. The goal of the present proposal is to validate HMGI-C (High Mobility Group I-C), an architectural transcription factor which regulates gene expression in tumorigenesis, as a drug target for colon cancer. The experimental approach will involve the inactivation of HMGI-C in Min mice, a widely accepted model of colon cancer resulting from an ethylnitrosurea (ENU) induced nonsense mutation at codon 850 of the murine Apc (adenomatous polyposis coli) gene. Germline mutations in humans in the APC gene are responsible for familial adenomatous polyposis, an inherited form of colon cancer. APC gene defects are also highly prevalent in sporadic colon tumors. It is hoped that inactivation of HMGI-C will attenuate colon cancer by inhibiting tumor formation or progression, thus validating HMGI-C as a drug target for colon cancer and setting the stage for a Phase II investigation into possible drug discovery. PROPOSED COMMERCIAL APPLICATION: Successful completion of this project would open up new prospects for the discovery of effective, clinically valuable drugs for the treatment of colon cancer which would have an enormous commercial potential. It is now estimated that in the United States alone, 129,400 new cases of colon cancer were reported, indicating the demand for safe, reliable pharmaceuticals.