Chemoprevention by a Targeted Thioredoxin Inhibitor.

描述（由申请人提供）： 预防早期癌症和治疗晚期癌症的许多分子靶点是相同的。因此，寻找新的预防剂的合乎逻辑的地方是用于治疗晚期癌症的靶向治疗剂，其中它们对人类受试者的毒性是已知的。我们已经开发了一种新的分子靶向治疗剂PX-12（2-甲基丙基2-咪唑基二硫化物）作为氧化还原信号蛋白硫氧还蛋白-1（Trx-1）的抑制剂。PX-12已经完成了针对晚期肿瘤的I期临床试验，在一些患者中显示肿瘤消退和病情稳定，现在正在进入II期试验。最重要的是，PX-12在患者中耐受性良好，毒性极小。Trx-1在多种早期和晚期人类癌症中过度表达，包括结肠癌、胃癌、胰腺癌、乳腺癌、肺癌和皮肤癌。在动物模型中，升高的Trx-1导致对致癌物的敏感性增加、肿瘤生长增加、对细胞凋亡的抗性和肿瘤血管生成增加。在患者肿瘤中，Trx-1升高与侵袭性肿瘤生长、细胞凋亡减少和患者存活率降低相关。我们发现，在模拟人类家族性腺瘤性息肉病（FAP）的ApcMin/+（多发性肠肿瘤）小鼠模型中，PX-12可显著减少肠道肿瘤的大小和数量，比目前批准的药物塞来昔布更有效。因此，我们的工作所基于的假设是，Trx-1在早期癌症中赋予抗死亡和促生长信号，因此，代表了化学预防的新靶点，并且Trx-1抑制剂PX-12将是预防结肠癌和其他人类癌症的有效药剂。这些研究的目的是对PX-12的作用进行机制研究，以获得口服PX-12对结肠癌和乳腺癌预防活性的临床前证据，以证明PX-12在化学预防动物模型中抑制其分子靶点的能力，并为PX-12的化学预防活性的机制提供证据。我们的总体目标是获得PX-12作为高风险或早期疾病患者的分子靶向预防剂的临床开发所需的信息。公共卫生相关性寻找新的癌症预防药物的一个合乎逻辑的地方是用于治疗晚期癌症的药物，其中对人类受试者的毒性是已知的。我们已经开发了一种新的治疗剂PX-12作为致癌蛋白硫氧还蛋白-1的抑制剂。PX-12最近在晚期癌症患者中完成了I期临床试验，显示毒性很小，具有抗肿瘤活性。拟议研究的目的是获得PX-12对早期结肠癌和乳腺癌预防活性的临床前证据。所获得的信息将用于PX-12作为高风险或早期疾病患者的癌症预防剂的临床开发。

DESCRIPTION (provided by applicant): Many of the molecular targets for the prevention of early cancer and for the therapy of advanced cancer are the same. Therefore, a logical place to seek new preventive agents is among the targeted therapeutic agents used for therapy of advanced cancer where their toxicity for human subjects is already known. We have developed a novel molecularly targeted therapeutic agent PX-12 (2-methylpropyl 2-imidazolyl disulfide) as an inhibitor of the redox signaling protein thioredoxin-1 (Trx-1). PX-12 has completed Phase I clinical trial against advanced tumors showing tumor regression and stable disease in a number of patients, and is now entering Phase II trial. Most importantly PX-12 is very well tolerated by patients with minimal toxicity. Trx-1 is over expressed in a wide variety of early and advanced human cancers including colon, gastric, pancreatic, breast, lung and skin cancer. In animal models elevated Trx-1 leads to increased sensitivity to carcinogens, increased tumor growth, resistance to apoptosis and increased tumor angiogenesis. In patient tumors elevated Trx-1 is associated with aggressive tumor growth, decreased apoptosis and decreased patient survival. We show that in the ApcMin/+ (multiple intestinal neoplasia) mouse model that mimics human familial adenomatous polyposis(FAP), PX-12 produces a marked decrease in the size and number of intestinal tumors, more effectively than the currently approved agent celecoxib . Thus, the hypothesis upon which our work is based is that Trx-1 imparts anti-death and pro-growth-signals in early cancer, thus, representing a novel target for chemoprevention, and that the Trx-1 inhibitor PX-12 will be an effective agent for the prevention of colon cancer and other human cancers. The objectives of the proposed studies are to conduct mechanistic investigations on the effects of PX-12, to obtain preclinical evidence for the preventive activity of orally administered PX-12 against colon and breast cancers, to demonstrate PX-12's ability to inhibit its molecular target(s) in the animal models of chemoprevention, and to provide evidence for the mechansim of PX-12's chemopreventive activity. Our overall goal is to obtain the information necessary for the clinical development of PX-12 as a molecularly targeted preventive agent for patients at high risk or with early disease. PUBLIC HEALTH RELEVANCE A logical place to seek new cancer preventive drugs is among the agents used for the therapy of advanced cancer where the toxicity for human subjects is already known. We have developed a novel therapeutic agent PX-12 as an inhibitor of the cancer causing protein thioredoxin-1. PX-12 has recently completed a Phase I clinical trial in patients with advanced cancer showing little toxicity and with antitumor activity. The objective of the proposed studies is to obtain preclinical evidence for the cancer preventive activity of PX-12 against early colon and breast cancer. The information obtained will be used for the clinical development of PX-12 as a cancer preventive agent for patients at high risk or with early disease.