PX-12, A Molecularly Targeted Preventive Agent

描述（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，但结直肠癌患者的5年生存率仅为50%左右，包括所有阶段。在过去的十年中，结肠直肠癌死亡率的小幅但真实的下降归因于更好的筛查。结直肠癌仍然是美国癌症相关死亡的第三大常见原因。对导致结肠癌发展和进展的分子途径的新理解使得能够开发针对这种常见恶性肿瘤的更有效的预防剂。ProlX制药公司提出开发作为结肠直肠癌的预防剂，PX-12，一种硫氧还蛋白-1（Trx-1）抑制剂，我们显示其抑制几种负责结肠癌发生的信号通路。PX-12具有预防剂所需的许多特性。其分子靶点和作用机制是已知的，易于生产，稳定性良好，在人体中具有可接受的安全性，并且有初步证据表明其在ApcMin/+小鼠肠癌模型中口服给药时具有预防活性。 拟议研究的目的是获得口服PX-12预防活性的临床前证据，并证明PX-12在结肠癌发生动物模型中抑制其分子靶点的能力。

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.