Chemoprevention by a Targeted Thioredoxin Inhibitor.

靶向硫氧还蛋白抑制剂的化学预防。

• 批准号: 7837614
• 负责人: GARTH POWIS
• 金额: $ 31.96万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-02 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7837614
• 关键词: Acute; Adenomatous Polyposis Coli; Advanced Malignant Neoplasm; Animal Model; Apoptosis; Azoxymethane; Biological Markers; Blood Vessels; Breast; Cancer Etiology; Carcinogens; Cardiotoxicity; Cell Proliferation Regulation; Cessation of life; Chemoprevention; Chemopreventive Agent; Clinical; Colon; Colon Carcinoma; Colorectal Cancer; Coxibs; Development; Disease; Disulfides; Genetic; Genus Cola; Goals; Growth; Human; Hypoxia; Hypoxia Inducible Factor; Inflammatory; Intestinal Neoplasms; Investigation; Lung; Malignant Neoplasms; Mammary Tumorigenesis; Modeling; Molecular Target; Mus; Non-Steroidal Anti-Inflammatory Agents; Oral; Oxidation-Reduction; PTGS2 gene; Pancreas; Patient Agents; Patient Selection; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Phase II Clinical Trials; Positioning Attribute; Prevention; Preventive; Proteins; Reporting; Resistance; Signal Pathway; Signal Transduction; Signaling Protein; Skin Cancer; Sodium Dextran Sulfate; Stable Disease; Stomach; Stress; Testing; Therapeutic Agents; Thioredoxin; Toxic effect; Tumor Angiogenesis; Work; advanced disease; base; cancer therapy; carcinogenesis; celecoxib; heart disease risk; high risk; human subject; inhibitor/antagonist; malignant breast neoplasm; mouse model; novel; novel therapeutics; pre-clinical; public health relevance; response; tumor; tumor growth

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.

描述（由申请人提供）： 许多用于预防早期癌症和晚期癌症治疗的分子靶标都是相同的。因此，寻求新的预防剂的逻辑场所是用于治疗晚期癌症治疗的靶向治疗剂之一，在该治疗中，他们对人类受试者的毒性已经知道。我们已经开发了一种新型的分子治疗剂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已完成I期临床试验，针对许多患者的肿瘤消退和稳定疾病的晚期肿瘤，现在正在参加II期试验。最重要的是，PX-12的毒性最小的患者非常耐受。 TRX-1在各种早期和晚期癌症中过度表达，包括结肠，胃，胰腺，乳腺癌，肺癌和皮肤癌。在动物模型中，提升TRX-1导致对致癌物的敏感性增加，肿瘤生长增加，对凋亡的抗性和增加的肿瘤血管生成。在患者肿瘤中，升高的TRX-1与侵袭性肿瘤生长有关，凋亡降低和患者生存率降低。我们表明，在模仿人类家族性腺瘤性息肉病（FAP）的Apcmin/+（多个肠道肿瘤）小鼠模型中，PX-12可产生明显减少的肠道肿瘤的大小和数量，比当前批准的药剂Celecoxib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和促增长信号，因此代表了化学预防的新靶标，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物。拟议的研究的目的是对PX-12的影响进行机械研究，以获得临床前的证据，以证明对结肠和乳腺癌的口服PX-12的预防活性，以证明PX-12抑制其分子靶标的PX-12的能力，以在化学生动的动物模型中为PXERTIVE提供了CHECTIVE of CHECTIVE of MEchansim of Mechansim of Mechansim of Px-12。我们的总体目标是获取PX-12作为高风险或早期疾病患者的分子预防剂的临床开发所需的信息。公共卫生相关性是寻求新的癌症预防药物的逻辑场所，是用于治疗晚期癌症的药物中的，在该治疗中，人们对人类受试者的毒性已经知道。我们已经开发了一种新型的治疗剂PX-12作为癌症抑制剂，引起蛋白硫氧还蛋白-1。 PX-12最近在晚期癌症患者中完成了I期临床试验，显示毒性很小和抗肿瘤活性。拟议的研究的目的是获得PX-12对早期结肠和乳腺癌的癌症预防活性的临床前证据。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。