EVALUATION OF TWO DIFFERENT CLASSES OF COMPOUNDS (STAT3 INHIBITORS AND SERMS) FOR THE PREVENTION OF URINARY BLADDER CANCER.

评估两类不同类型的化合物（STAT3 抑制剂和 Serms）预防膀胱癌的作用。

• 批准号: 10674662
• 负责人: Chinthalapally V. Rao
• 金额: $ 24.41万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-21 至 2024-02-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10674662
• 关键词: Affinity; Animals; Apoptosis; Biological Markers; Bladder Neoplasm; Cell Proliferation; Cell Survival; Chemopreventive Agent; Development; Disease; Dominant-Negative Mutation; Dose; Estradiol; Estrogen Receptor Modulators; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Family; Immune response; In Vitro; Incidence; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Methylnitrosourea; Modeling; Mus; Muscle; Nitrosamines; Normal Cell; Organ; Patients; Prevention; Process; Rattus; Recurrence; Reporting; Research; Rodent Model; Role; Selective Estrogen Receptor Modulators; Stat3 protein; Supporting Cell; Tissue Sample; Travel; United States; Urinary system; analog; bladder cancer prevention; cancer type; carcinogenesis; efficacy testing; inhibitor; malignant breast neoplasm; member; novel; pharmacodynamic biomarker; preventive intervention; receptor; research and development; statistics; transcription factor; tumor

Urinary bladder cancer is one of the most prevalent malignancies of the urinary system, with over 80,000 new cases predicted in the United States in 2019 (https://www.cancer.org/cancer/bladder-cancer/about/key-statistics.html). Although 70% of patients initially present with non-muscle-invasive disease, urinary bladder tumors have a high rate of recurrence (50 –70%), and 10-15% will progress to muscle-invasive disease within a 5-year period, making the prevention of bladder cancer an important priority. Throughout the years, a relatively large number of compounds have been tested for efficacy in the prevention of early stage bladder cancers. However, many of these agents have proven to be largely ineffective or toxic to various organs. Thus, there is a need for the identification of new chemopreventive agents with novel mechanisms of action. Estrogen receptor α (ERα) is expressed in 18% of patients with bladder cancer and is associated with highly proliferative tumors and lower overall survival; ERβ is expressed in 63% of bladder cancer tumors, and the degree of ERβ expression increases with increasing stage and grade of differentiation. These correlations, combined with the findings that N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-treated mice lacking ERβ have a reduced incidence of bladder cancer, suggest that the ER could serve as a target for preventive intervention. In support of this, several groups have reported that estrogen receptor modulators reduce bladder cancer cell proliferation in vitro, and reduce cancer incidence in BBN-treated mice. This Task Order will evaluate the selective estrogen receptor modulator bazedoxifene for bladder cancer prevention. Bazedoxifene has affinity for both the ERα and ERβ receptors, and it is a competitive inhibitor of 17-β-estradiol at either estrogen receptor. It is also highly effective as a chemopreventive agent in the N-Nitroso-N-methylurea (MNU)-rat model, in which breast cancer development is driven by expression of the ER. Signal transducer and activator of transcription 3 (STAT3) is one of the seven members of a family of transcription factors that regulates cell proliferation, differentiation, apoptosis, and the immune response. Although the activation of STAT3 is transient and highly regulated in normal cells, it is constitutively active in several types of cancer, including bladder cancer. The findings that the expression of dominant-negative STAT3 inhibits bladder tumor formation and that the STAT3 inhibitor WP1066 reduces cell survival and proliferation of bladder cancer cells support a role for STAT3 in bladder cancer carcinogenesis and suggest that STAT3 could serve as a target for preventive intervention. This Task Order will also investigate the chemopreventive potential of STAT3 inhibitors such as GLG-302,SH5-07, YHO-1701, C188-9, and others that are in the process of being developed by the Chemopreventive Agent Development Research Group.

泌尿囊性癌是尿液系统中最普遍的恶性肿瘤之一，2019年美国预计将有80,000例新病例（https://www.cancer.org/cancer.org/cancer/bladder-cancer/bladder-cancer/about-cancer/about/key-statistics.html）。尽管有70％的患者最初出现非肌肉侵入性疾病，但泌尿膀胱肿瘤的复发率很高（50 –70％），而10-15％的患者将在5年内发展为肌肉侵入性疾病，这使得预防膀胱癌的预防是重要的。多年来，已经对相对大量化合物进行了测试，以预防早期膀胱癌的效率。但是，这些代理中的许多被证明在很大程度上对各种器官无效或有毒。这是需要鉴定具有新型作用机理的新化学预防剂。 雌激素受体α（ERα）在18％的膀胱癌患者中表达，并与高度增殖的肿瘤和较低的总生存期有关。 ERβ在63％的膀胱癌肿瘤中表达，ERβ表达程度随着分化的阶段和等级的增加而增加。这些相关性以及发现N-丁基N-（4-羟基丁基） - 硝酸胺（BBN）处理的缺乏ERβ的小鼠的相关性降低了膀胱癌的发病率，这表明ER可以作为预防性干预的靶标。为了支持这一点，几个小组报告说，雌激素受体调节剂在体外减少了膀胱癌细胞的增殖，并降低了BBN处理的小鼠的癌症发病率。该任务顺序将评估选择性雌激素受体调节剂BAZEDFENE，以预防膀胱癌。 Bazedoxifene对ERα和ERβ受体具有亲和力，并且在任何一种雌激素受体下都是17-β-雌二醇的竞争抑制剂。它在N-硝基-N-甲基脲（MNU）-RAT模型中也是一种化学预防剂，在该模型中，乳腺癌的发展是由ER表达驱动的。 转录3（STAT3）的信号换能器和激活因子是调节细胞增殖，分化，凋亡和免疫响应的七个转录因子家族的成员之一。尽管STAT3的激活是短暂的，并且在正常细胞中高度调节，但在包括膀胱癌在内的几种类型的癌症中，它具有组成性活跃。显性阴性STAT3的表达的发现抑制了膀胱肿瘤的形成，而STAT3抑制剂WP1066降低了细胞的存活和膀胱癌细胞的增殖支持STAT3在膀胱癌癌发生中的作用，并建议STAT3可以作为预防干预的靶标。该任务顺序还将调查STAT3抑制剂（例如GLG-302，SH5-07，YHO-1701，C188-9）的化学预防潜力，以及由化学探测剂开发研究小组开发的其他过程。