EGFR Blockade in Endometrial Cancer

描述(申请人提供)：晚期子宫内膜癌是致命的 2000年有7000多名妇女死于这种疾病。没有新的治疗方法 养生法已经有很多年了。子宫内膜癌的生长 受类固醇激素雌激素和雌激素之间复杂的相互作用控制 黄体酮和生长因子，特别是表皮生长因子 (EGF)。阻断EGF受体(EGFR)的新分子的开发已经 现在提供了在晚期患者中测试这种药物的机会 未通过标准治疗的子宫内膜癌患者。作为对一项 应国家癌症研究所(CTEP)的邀请，我们设计了一个 药物ZD1839(易瑞沙)的第二阶段合作试验将在 由妇科肿瘤学小组(GOG)赞助。与 将进行临床试验、翻译和基础调查。这个 提出了以下具体目标。(1)我们将进行第二阶段 评价ZD1839的疗效和安全性的开放标签试验 晚期或复发子宫内膜癌56例。校长 经检验的假设是，ZD1839将显著增加 存活且无进展的晚期子宫内膜癌患者 六个月。(2)测定ZD1839对生物的影响 包含试验的次要终结点的关联。其中包括EGFR， 磷酸化的表皮生长因子受体、雌激素受体和孕激素受体 在治疗前后的组织活检中，以及ZD1839的水平， ZD1839活性和血清中可溶性EGFR。ZD1839活动将是 与体外磷酸化试验相近。我们将检验这些假设 ZD1839阻断了EGFR的磷酸化，EGFR导致了 ZD1839处理保存的ER和PR的调节。可能的 表皮生长因子激活MAP激酶通路与血管紧张素转换酶失活 子宫内膜癌中的激素受体是这一提议的一个新焦点。(3) 我们将评估EGF和ZD1839对细胞增殖、信号转导、 子宫内膜癌中的基因表达、报告基因激活与细胞凋亡 细胞系。ZD1839进一步使细胞对生长敏感的能力 紫杉醇和黄体酮的限制作用将被研究。目标是 这些研究中的一项是评估一种治疗糖尿病的新药 子宫内膜癌，研究其作用和与其他疾病的潜在协同作用 在实验室中的治疗，并产生数据，可能会改善治疗 未来。

DESCRIPTION (provided by applicant): Advanced endometrial cancer is a lethal disease from which over 7,000 women died in the year 2000. No novel treatment regimens have become available in many years. The growth of endometrial cancer is controlled by complex interactions between the steroid hormones estrogen and progesterone and growth factors, particularly the epidermal growth factor (EGF). The development of new molecules to block the EGF receptor (EGFR) has now provided an opportunity to test such agents in patients with advanced endometrial cancers who have failed standard therapy. In response to an invitation from the National Cancer Institute (CTEP), we have designed a cooperative phase II trial of the drug ZD1839 (Iressa) to be carried out under the auspices of the Gynecologic Oncology Group (GOG). In conjunction with the clinical trial, translational and basic investigations will be performed. The following Specific Aims are proposed. (1) We will carry out a phase II open-label trial evaluating the efficacy and safety of ZD1839 in approximately 56 patients with advanced or recurrent endometrial cancer. The principal hypothesis tested is that ZD1839 will significantly increase the number of patients with advanced endometrial cancer who are alive and progression-free at six months. (2) We will determine the effects of ZD1839 on biological correlates that comprise secondary endpoints for the trial. These include EGFR, phosphorylated EGFR, estrogen receptors (ER), and progesterone receptors (PR) in pre- and post treatment tissue biopsies, as well as the levels of ZD1839, ZD1839 activity, and soluble EGFR in serum samples. ZD1839 activity will be approximated by an ex vivo phosphorylation assay. We will test the hypotheses that ZD1839 blocks EGFR phosphorylation and that EGFR results in the down regulation of ER and PR that are preserved with ZD1839 treatment. The possible link between the activation of the MAP kinase pathway by EGF and the loss of hormone receptors in endometrial cancer is a novel focus of this proposal. (3) We will evaluate the effects of EGF and ZD1839 on proliferation, signaling, gene expression, reporter gene activation, and apoptosis in endometrial cancer cell lines. The ability of ZD1839 to further sensitize the cells to the growth limiting effects of paclitaxel and progesterone will be investigated. The goal of these studies is to evaluate a new medication for the treatment of endometrial cancer, investigate its action and potential synergy with other therapies in the laboratory, and generate data that may improve therapy in the future.