EGFR Blockade in Endometrial Cancer

描述（由申请人提供）：晚期子宫内膜癌是一种致命的 2000年有7,000多名妇女死于这种疾病。无新治疗 许多年来已经有了治疗方案。子宫内膜癌的早期症状 是由类固醇激素雌激素和 孕酮和生长因子，特别是表皮生长因子 （EGF）。开发新的分子来阻断EGF受体（EGFR）， 现在提供了一个机会，以测试这些药物在患者的先进的 标准治疗失败的子宫内膜癌患者。响应于 应国家癌症研究所（CTEP）的邀请，我们设计了一个 药物ZD 1839（易瑞沙）的合作II期试验将在 妇科肿瘤组（GOG）的赞助。联同 将进行临床试验、转化和基础研究。的 提出了以下具体目标。(1)我们将进行第二阶段 一项评价ZD 1839在约100名受试者中的疗效和安全性的开放标签试验 56例晚期或复发性子宫内膜癌患者。校长 假设测试的是，ZD 1839将显着增加的数量， 晚期子宫内膜癌患者存活且无进展， 六个月(2)我们将确定ZD 1839对生物学的影响， 构成试验次要终点的相关性。这些包括EGFR， 磷酸化EGFR、雌激素受体（ER）和孕酮受体（PR） 在治疗前和治疗后的组织活检中，以及ZD 1839的水平， 血清样品中的ZD 1839活性和可溶性EGFR。ZD 1839活动将是 通过离体磷酸化测定近似。我们将检验 ZD 1839阻断EGFR磷酸化，EGFR导致 ZD 1839处理保留的ER和PR调节。可能的 EGF激活MAP激酶通路与EGF缺失之间的联系 子宫内膜癌中的激素受体是该提议的新焦点。（三） 我们将评估EGF和ZD 1839对增殖、信号传导、 子宫内膜癌的基因表达、报告基因激活和细胞凋亡 细胞系ZD 1839进一步使细胞对生长敏感的能力 将研究紫杉醇和孕酮的限制作用。目标 这些研究的目的是评估一种新的药物， 子宫内膜癌，研究其作用和与其他 在实验室中的治疗，并产生数据，可以改善治疗， 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.