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

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。虽然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%），10-15%的患者会在5年内进展为肌肉浸润性疾病，这使得预防膀胱癌成为一个重要的优先事项。多年来，已经测试了相对大量的化合物在预防早期膀胱癌中的功效。然而，这些药剂中的许多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，并与高度增殖性肿瘤和较低的总生存期相关; ERβ在63%的膀胱癌肿瘤中表达，ERβ表达程度随分期和分化程度的增加而增加。这些相关性，结合N-butyl-N-（4-hydroxybutyl）-nitrosamine（BBN）处理的缺乏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靶点。为了支持这一点，几个研究小组已经报道了雌激素受体调节剂在体外减少膀胱癌细胞增殖，并降低BBN治疗小鼠的癌症发病率。本任务单将评估选择性雌激素受体调节剂苯多昔芬预防膀胱癌的作用。巴多昔芬对ERα和ERβ受体均具有亲和力，是17-β-雌二醇对任一雌激素受体的竞争性抑制剂。它在N-亚硝基-N-甲基脲（MNU）-大鼠模型中也是非常有效的化学预防剂，其中乳腺癌的发展是由ER的表达驱动的。 信号转导子和转录激活子3（STAT 3）是调节细胞增殖、分化、凋亡和免疫应答的转录因子家族的七个成员之一。尽管STAT 3的激活在正常细胞中是短暂的和高度调节的，但它在包括膀胱癌在内的几种类型的癌症中是组成型活性的。显性负性STAT 3的表达抑制膀胱肿瘤的形成以及STAT 3抑制剂WP 1066降低膀胱癌细胞的细胞存活和增殖的发现支持了STAT 3在膀胱癌发生中的作用，并表明STAT 3可以作为预防性干预的靶点。本任务指令还将研究STAT 3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降低了乳腺癌MMTV-Neu小鼠模型中的肿瘤多样性，据报道，其结构类似物（包括SH 5 -07、BP-1-102和SH 4 -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这类STAT 3抑制剂。

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.