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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CONC (01))
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Wu, Roy S
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University of New Mexico
Obstetrics & Gynecology
Schools of Medicine
United States
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Devor, Eric J; Cha, Elizabeth; Warrier, Akshaya et al. (2018) The miR-503 cluster is coordinately under-expressed in endometrial endometrioid adenocarcinoma and targets many oncogenes, cell cycle genes, DNA repair genes and chemotherapy response genes. Onco Targets Ther 11:7205-7211
Ebeid, Kareem; Meng, Xiangbing; Thiel, Kristina W et al. (2018) Synthetically lethal nanoparticles for treatment of endometrial cancer. Nat Nanotechnol 13:72-81
Devor, Eric J; Miecznikowski, Jeffrey; Schickling, Brandon M et al. (2017) Dysregulation of miR-181c expression influences recurrence of endometrial endometrioid adenocarcinoma by modulating NOTCH2 expression: An NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol 147:648-653
Devor, Eric J; Reyes, Henry D; Gonzalez-Bosquet, Jesus et al. (2017) Placenta-Specific Protein 1 Expression in Human Papillomavirus 16/18-Positive Cervical Cancers Is Associated With Tumor Histology. Int J Gynecol Cancer 27:784-790
Li, Yujun; Gonzalez Bosquet, Jesus; Yang, Shujie et al. (2017) Role of metadherin in estrogen-regulated gene expression. Int J Mol Med 40:303-310
Devor, Eric J; Gonzalez-Bosquet, Jesus; Warrier, Akshaya et al. (2017) p53 mutation status is a primary determinant of placenta-specific protein 1 expression in serous ovarian cancers. Int J Oncol 50:1721-1728
Reyes, Henry D; Miecznikowski, Jeffrey; Gonzalez-Bosquet, Jesus et al. (2017) High stathmin expression is a marker for poor clinical outcome in endometrial cancer: An NRG oncology group/gynecologic oncology group study. Gynecol Oncol 146:247-253
Dai, Donghai; Thiel, Kristina W; Salinas, Erin A et al. (2016) Stratification of endometrioid endometrial cancer patients into risk levels using somatic mutations. Gynecol Oncol 142:150-157
Devor, Eric J; Schickling, Brandon M; Reyes, Henry D et al. (2016) Cullin-5, a ubiquitin ligase scaffold protein, is significantly underexpressed in endometrial adenocarcinomas and is a target of miR-182. Oncol Rep 35:2461-5
Gonzalez Bosquet, Jesus; Newtson, Andreea M; Chung, Rebecca K et al. (2016) Prediction of chemo-response in serous ovarian cancer. Mol Cancer 15:66

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