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

膀胱癌是最常见的泌尿系统恶性肿瘤之一，预计2019年美国将有超过8万新病例。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%的患者将在5年内进展为肌肉侵袭性疾病，这使得预防膀胱癌成为重要的优先事项。多年来，已有相当数量的化合物在预防早期膀胱癌方面进行了有效性测试。然而，其中许多药物已被证明在很大程度上是无效的或对各种器官有毒。因此，有必要确定具有新的作用机制的新的化学预防药物。 雌激素受体α(ERα)在18%的膀胱癌患者中表达，与高增殖性肿瘤和低总生存率有关；ERβ在63%的膀胱癌患者中表达，且ERβ的表达程度随分化程度和分期的增加而增加。这些相关性，再加上N-丁基-N-(4-羟基丁基)-亚硝胺(BBN)处理的缺乏ERβ的小鼠膀胱癌发病率降低的发现，表明ER可以作为预防干预的目标。为了支持这一点，几个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的增殖，并降低了BBN治疗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巴多昔芬预防膀胱癌。巴多昔芬对ERα和ERβ受体均有亲和力，是17-β-雌二醇在这两种受体上的竞争性抑制剂。在N-亚硝基-N-甲基脲(MNU)-大鼠模型中，它也是一种高效的化学预防药物，在该模型中，乳腺癌的发生是由ER的表达驱动的。 信号转导和转录激活因子3(STAT3)是调控细胞增殖、分化、凋亡和免疫反应的转录因子家族的7个成员之一。虽然STAT3的激活在正常细胞中是短暂的，并且受到高度调控，但它在包括膀胱癌在内的几种类型的癌症中都是结构性活跃的。研究结果表明，显性负性STAT3的表达抑制了膀胱癌的形成，STAT3抑制剂WP1066降低了膀胱癌细胞的存活和增殖，支持了STAT3在膀胱癌发生中的作用，提示STAT3可以作为预防干预的靶点。该任务还将研究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。在MMTV-Neu小鼠乳腺癌模型中，GLG-302降低了肿瘤的多样性，其结构类似物包括SH5-07、BP-1-102和SH4-54，据报道具有改善的生物利用度和体外效力。化学预防药物开发研究组目前正在进一步优化这类STAT3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.