PX-12, A Molecularly Targeted Preventive Agent

描述（由申请人提供）：2001年，美国估计有135,400人患结直肠癌，56,700人死于该疾病。尽管在开发更好的化疗方案和诊断方法方面取得了一些进展，但包括所有阶段在内，结直肠癌患者的5年生存率仅为50%左右。在过去十年中，结直肠癌死亡率的小幅下降是由于更好的筛查。在美国，结直肠癌仍然是癌症相关死亡的第三大常见原因。对导致结肠癌发生和发展的分子途径的新认识，使这种常见恶性肿瘤的更有效预防药物的开发成为可能。ProlX制药公司提出开发一种预防结直肠癌的药物PX-12，这是一种硫氧还蛋白-1 （Trx-1）抑制剂，我们发现它可以抑制几种导致结肠癌发生的信号通路。PX-12具有许多预防剂所需的特性。其分子靶点和作用机制已知，制备容易，稳定性好，在人体内具有可接受的安全性，在ApcMin/+小鼠肠癌模型中口服具有预防作用。

DESCRIPTION (provided by applicant): An estimated 135,400 people developed colorectal cancer in the US in the year 2001 and 56,700 died of the disease. Despite some progress in developing better chemotherapy regimens and diagnostic methods, the 5-year survival rate in patients with colorectal cancer is only about 50 %, all stages included. A small but real decline in mortality from colorectal cancer over the last decade has been attributed to better screening. Colorectal cancer remains the third most common cause of cancer related death in the US. New understanding of the molecular pathways leading to the development and progression of colon cancer is enabling the development of more effective preventive agents for this common malignancy. ProlX Pharmaceuticals proposes to develop as a preventive agent for colorectal cancer, PX-12, a thioredoxin-1 (Trx-1) inhibitor, that we show inhibits several of the signaling pathways responsible for colon carcinogenesis. PX-12 has many characteristics required of a preventive agent. Its molecular target and mechanism of action are known, it is easy to manufacture and has good stability, it has an acceptable safety profile in humans and there is preliminary evidence for its preventive activity when administered orally in the ApcMin/+ mouse model of intestinal cancer. The goal of the proposed studies is to obtain preclinical evidence of the preventive activity of orally administered PX-12 and to demonstrate PX-12's ability to inhibit its molecular targets in animal models of colon carcinogenesis.