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

任务顺序：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: 10020556
• 负责人: CLINTON GRUBBS
• 金额: $ 61.51万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2021-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020556
• 关键词: Affinity; Animal Model; Apoptosis; Biological Availability; Biological Markers; Bladder Neoplasm; Breast Cancer Model; Cell Proliferation; Cell Survival; Chemopreventive Agent; Development; Disease; Dominant-Negative Mutation; Dose; Estradiol; Estrogen Receptor Modulators; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Evaluation; Family; Immune response; In Vitro; Incidence; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Methylnitrosourea; Modeling; Mouse Mammary Tumor Virus; Mus; Muscle; Nitrosamines; Normal Cell; Organ; Patients; Prevention; Preventive Intervention; Process; Rattus; Recurrence; Reporting; Research; Role; Selective Estrogen Receptor Modulators; Stat3 protein; Structure; Supporting Cell; Travel; United States; Urinary system; analog; bladder cancer prevention; cancer type; carcinogenesis; efficacy testing; human model; improved; inhibitor/antagonist; malignant breast neoplasm; member; mouse model; novel; receptor; research and development; 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. 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 the STAT3 inhibitor GLG-302 and its structural analogs in a model of human bladder cancer. GLG-302 reduces tumor multiplicity in the MMTV-Neu mouse model of mammary cancer, and its structural analogs, including SH5-07, BP-1-102, and SH4-54, are reported to have improved bioavailability and in vitro potency. The Chemopreventive Agent Development Research Group is currently in the process of further optimizing this class of STAT3 inhibitors.

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80,000例新发病例。尽管70%的患者最初表现为非肌肉浸润性疾病，但膀胱肿瘤的复发率很高（50-70%），并且10-15%将在5年内进展为肌肉浸润性疾病，因此预防膀胱癌成为重要的优先事项。多年来，已经测试了相对大量的化合物在预防早期膀胱癌方面的功效。然而，许多这些药物已被证明对各种器官基本上无效或有毒。因此，需要鉴定具有新作用机制的新化学预防剂。 雌激素受体 α (ERα) 在 18% 的膀胱癌患者中表达，与高度增殖的肿瘤和较低的总生存率相关； ERβ在63%的膀胱癌肿瘤中表达，并且ERβ表达程度随着分化阶段和级别的增加而增加。这些相关性，再加上 N-丁基-N-(4-羟丁基)-亚硝胺 (BBN) 治疗缺乏 ERβ 的小鼠膀胱癌发病率降低的发现，表明 ER 可以作为预防性干预的目标。为了支持这一点，一些研究小组报告称，雌激素受体调节剂可以减少体外膀胱癌细胞的增殖，并降低接受 BBN 治疗的小鼠的癌症发病率。该任务令将评估选择性雌激素受体调节剂巴多昔芬用于预防膀胱癌的作用。巴多昔芬对 ERα 和 ERβ 受体均具有亲和力，并且是任一雌激素受体上 17-β-雌二醇的竞争性抑制剂。在 N-亚硝基-N-甲基脲 (MNU) 大鼠模型中，它作为化学预防剂也非常有效，在该模型中，乳腺癌的发展是由 ER 的表达驱动的。 信号转导和转录激活因子 3 (STAT3) 是调节细胞增殖、分化、凋亡和免疫反应的转录因子家族的七个成员之一。尽管 STAT3 的激活在正常细胞中是短暂的且受到高度调控，但它在包括膀胱癌在内的多种类型的癌症中持续活跃。显性失活 STAT3 的表达抑制膀胱肿瘤形成以及 STAT3 抑制剂 WP1066 降低膀胱癌细胞的细胞存活和增殖的发现支持 STAT3 在膀胱癌致癌过程中的作用，并表明 STAT3 可以作为预防性干预的靶点。该任务令还将研究 STAT3 抑制剂 GLG-302 及其结构类似物在人类膀胱癌模型中的化学预防潜力。 GLG-302 降低了 MMTV-Neu 小鼠乳腺癌模型中的肿瘤多样性，据报道其结构类似物（包括 SH5-07、BP-1-102 和 SH4-54）具有改善的生物利用度和体外效力。化学预防剂开发研究小组目前正在进一步优化此类STAT3抑制剂。