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

描述（由申请人提供）：结肠癌是美国的一个主要健康问题，1999年报告的新病例估计为129，400例。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。这种疾病的成功管理将需要发现安全有效的药物。本提案的目标是验证HMGI-C（高迁移率族I-C），一种在肿瘤发生中调节基因表达的结构转录因子，作为结肠癌的药物靶标。 实验方法将涉及Min小鼠中HMGI-C的失活，Min小鼠是一种广泛接受的结肠癌模型，由乙基亚硝基脲（ENU）诱导的小鼠Apc（腺瘤性结肠息肉病）基因密码子850处的无义突变引起。人类APC基因的生殖系突变是家族性腺瘤性息肉病（一种遗传性结肠癌）的原因。APC基因缺陷在散发性结肠肿瘤中也非常普遍。希望HMGI-C的失活将通过抑制肿瘤形成或进展来减弱结肠癌，从而验证HMGI-C作为结肠癌的药物靶标，并为可能的药物发现的II期研究奠定基础。 拟定商业应用： 该项目的成功完成将为发现具有巨大商业潜力的治疗结肠癌的有效、临床价值的药物开辟新的前景。 据估计，仅在美国，就有129，400例结肠癌新病例报告，这表明对安全可靠药物的需求。

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.