CLINICAL TRIAL: PHASE II STUDY OF TAMOXIFEN FOR PROGRESSIVE TRANSITIONAL CELL C

临床试验：他莫昔芬治疗进行性移行细胞 C 的 II 期研究

• 批准号: 8356767
• 负责人: SETH P. LERNER
• 金额: $ 0.2万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356767
• 关键词: Americas; Animal Model; Apoptosis; Bladder Neoplasm; Cancer cell line; Cell Line; Clinical Research; Clinical Trials; Dimensions; Dose; Estrogen Receptors; Fatty acid glycerol esters; Female; Freedom; Funding; Grant; Human; Implant; In Vitro; Inbred BALB C Mice; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mammary gland; Measurable; Microarray Analysis; Mus; National Center for Research Resources; Oral; Patients; Placebos; Platinum; Principal Investigator; Raloxifene; Regimen; Research; Research Infrastructure; Resources; Safety; Selective Estrogen Receptor Modulators; Site; Solvents; Source; Staging; Tamoxifen; Time; Tissue Microarray; Toxic effect; Transitional Cell; Transitional Cell Carcinoma; Tumor Volume; United States National Institutes of Health; Xenograft Model; base; cancer cell; cohort; cost; innovation; phase 2 study; receptor expression; research study; response; subcutaneous; therapeutic target; tumor; tumor growth

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT We have demonstrated that estrogen receptor (ER)-B is expressed in RT-4, 5637, T-24, TSU-PR1 and TCC-SUP human bladder cancer cell lines, while ER-a is expressed at verylow levels. Raloxifene, a SERM (selective estrogen receptor modulator) induced apoptosis and decreased the viability of RT-4, T-24, and 5637 cell-lines in-vitro in a dose dependent manner. Using tissue microarray analysis, ER-B was expressed in 133 (63.3%) of 210 bladder tumors, while ER-a was expressed in only 2 tumors. The expression of ER-B was associated withhigher stage and grade. We constructed a muring xenograft model bearing human bladder cancer to evaluate the efficacy of SERMs in an animal model. A total of 10 5637 human transitional cell carcinoma cells were injected into one site at a mammary fat pad of 6-8 week old female athymic BALB/c nu/nu mice. Only mice that developed measurable subcutaneous tumor (at least 3 mm in one dimension) within 2 weeks were chosen for further study. Five cohorts of mice consisting of 6-8 mice per cohort were administered no therapy, palcebo (solvent only), raloxifene 0.01 mg/day, raloxifene 0.1 mg/day and raloxifene 1 mg/day for 5 days a week by oral gavage for 8 weeks. All of the doses of raloxifene significantly inhibited the growth of tumor (p0.05). In a second experiment, four cohorts of mice with measurable tumors with 10 mice per cohort were implanted withsubcutaneous 60-day time-release pellets (innovative Research of America, Sarasota, FL) delivering placebo, tamoxifen 0.008 mg/day, tamoxifen 0.125 mg/day and tamoxifen 1.25 mg/day, respectively. Again, significant inhibition of tumor was observed with all of the doses of tamoxifen (p0.01). In a separate third confirmatory experiment, four cohorts of mice with 10 mice per cohort (with statistically similar tumor volumes) were implanted with subcutaneous 60-day time-release pellets (Innovative Research of America, Sarasota, FL) delivering placebo, tamoxifen 0.008 mg/day (low dose), tamoxifen 0.125 mg/day (medium dose) and raloxifene 0.1 mg/day, respectively. The tamoxifen or raloxifene treated mice demonstrated significantly smaller tumors compared to placebo (P0.05). The expression of estrogen receptors in human bladder cancers in conjunction with the anti-tumor activity of SERMs both in vitro and in a murine xenograft model bearing human bladder cancer cells provides the rationale for evaluating tamoxifen as a targeted therapeutic for patients with bladder cancer. HYPOTHESIS Tamoxifen, a selective estrogen receptor modulator (SERM), may have anti-tumor activity against human transitional cell carcinoma owing to estrogen receptor (ER)-B receptor expression by this malignancy. SPECIFIC AIMS Primary objective: To assess the 4 month freedom fromprogression (FFP) from tamoxifen in progressive transitional cell cancer following platinum-based therapy Secondary objectives: To determine ojbective response rate To assess the association of FFP with ER-B status of the tumor To assess the toxicity/safety profile of this regimen To assess overall survival (OS)

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 摘要 我们已经证明，雌激素受体（ER）-B在RT-4、5637、T-24、TSU-PR 1和TCC-10人膀胱癌细胞系中表达，而ER-α以非常低的水平表达。 雷洛昔芬，SERM（选择性雌激素受体调节剂）诱导凋亡，并降低RT-4，T-24，和5637细胞系在体外的剂量依赖性方式的活力。 采用组织芯片分析，ER-B在210例膀胱肿瘤中表达133例（63.3%），而ER-a仅在2例膀胱肿瘤中表达。 ER-B的表达与肿瘤的分期、分级有关。 我们构建了一个荷人膀胱癌的小鼠异种移植模型，以评估SERM在动物模型中的疗效。 将总共105637个人移行细胞癌细胞注射到6-8周龄雌性无胸腺BALB/c nu/nu小鼠的乳房脂肪垫的一个部位。 仅选择在2周内形成可测量的皮下肿瘤（在一个维度上至少3 mm）的小鼠用于进一步研究。 由每组6-8只小鼠组成的五组小鼠通过口服管饲法每周5天给予无治疗、Palcebo（仅溶剂）、雷洛昔芬0.01 mg/天、雷洛昔芬0.1 mg/天和雷洛昔芬1 mg/天，持续8周。 所有剂量的雷洛昔芬均能显著抑制肿瘤生长（p0.05）。 在第二个实验中，四组具有可测量肿瘤的小鼠（每组10只小鼠）皮下植入60天定时释放丸剂（Innovative Research of America，Sarasota，FL），分别递送安慰剂、他莫昔芬0.008 mg/天、他莫昔芬0.125 mg/天和他莫昔芬1.25 mg/天。 同样，所有剂量的他莫昔芬均观察到显著的肿瘤抑制作用（p <0.01）。 在单独的第三验证性实验中，将四组小鼠（每组10只小鼠，具有统计学上相似的肿瘤体积）植入皮下60天定时释放丸剂（Innovative Research of America，Sarasota，FL），分别递送安慰剂、他莫昔芬0.008 mg/天（低剂量）、他莫昔芬0.125 mg/天（中等剂量）和雷洛昔芬0.1 mg/天。 与安慰剂相比，他莫昔芬或雷洛昔芬治疗的小鼠显示出显著更小的肿瘤（P0.05）。 雌激素受体在人膀胱癌中的表达以及SERM在体外和在携带人膀胱癌细胞的鼠异种移植模型中的抗肿瘤活性为评价他莫昔芬作为膀胱癌患者的靶向治疗提供了理论基础。 假设 他莫昔芬是一种选择性雌激素受体调节剂（SERM），由于其表达的雌激素受体（ER）-B受体而对人移行细胞癌具有抗肿瘤活性。 具体目标 主要目标：评估他莫昔芬治疗以铂类为基础的进行性移行细胞癌后4个月的无进展（FFP） 次要目的： 确定有效应答率 评估FFP与肿瘤ER-B状态的相关性 评估该方案的毒性/安全性特征 评估总生存期（OS）