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: 10269139
• 负责人: Chinthalapally V. Rao
• 金额: $ 66.63万
• 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 2022-09-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10269139
• 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; Estrogen receptor positive; Family; Immune response; In Vitro; Incidence; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Methylnitrosourea; Modeling; Mus; Muscle; Nitrosamines; Normal Cell; Organ; Patients; Prevention; Preventive Intervention; 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/antagonist; malignant breast neoplasm; member; novel; pharmacodynamic biomarker; 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.

膀胱癌是泌尿系统最常见的恶性肿瘤之一，预计2019年美国将有超过8万例新病例（https://www.cancer.org/cancer/bladder-cancer/about/key-statistics.html）。虽然70%的患者最初表现为非肌肉侵袭性疾病，但膀胱肿瘤的复发率很高（50 -70%），10-15%的患者在5年内会发展为肌肉侵袭性疾病，因此预防膀胱癌是重中之重。多年来，相对大量的化合物在预防早期膀胱癌的功效方面进行了测试。然而，这些药物中的许多已被证明在很大程度上是无效的或对各种器官有毒。因此，有必要鉴定具有新的作用机制的新的化学预防剂。