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The University of Texas M.D. Anderson Cancer Center SPORE in Uterine Cancer Karen H. Lu, M.D. Purpose and Intent Endometrial cancer is the most common gynecologic malignancy and the fourth most common cancer in women. For 2004, there will be an estimated 40,320 women diagnosed with this disease and 7,090 deaths. Significantly, there has been no decrease in the incidence or mortality of this cancer over the last 15 years. The goal of the Gynecological Cancer SPORE at the University of Texas – M.D. Anderson Cancer Center is to conduct innovative translational research for the prevention and treatment of uterine tumors. Tumors arising from the epithelial (endometrium) and smooth muscle (myometrium) compartments of the uterus are important, yet under-funded, causes of morbidity and mortality in the United States. Endometrial cancer is the most common gynecologic malignancy and the fourth most common cancer in women. For 2004, there will be an estimated 40,320 women diagnosed with this disease and 7,090 deaths. Significantly, there has been no decrease in the incidence or mortality of this cancer over the last 15 years. The proposed Gynecological Cancer SPORE is a truly multidisciplinary program that includes clinicians and basic scientists with both oncologic and non-oncologic backgrounds. Such a multidisciplinary team is necessary to achieve a more thorough understanding of the pathogenesis, prevention, and treatment of these tumors. Encompassed within this overall goal are the following goals of the program:
Project 1 Background: Epidemiologic evidence has identified unopposed estrogen exposure as a risk factor associated with endometrial carcinogenesis. A significant proportion of endometrial adenocarcinomas express immunohistochemically detectable estrogen (ER) and progesterone (PR) receptors, and objective clinical responses to “antiestrogenic” therapy using progestational agents (Megace) are well documented. The availability of SERMs that exhibit tissue-specific agonist or antagonist profiles now permits a more targeted approach to interference with (ER) signaling. One of these SERMs, LY353381 (Arzoxifene) developed by Eli Lilly, has been shown to function as an antagonist in the uterus in preclinical studies, although the molecular mechanisms response for this antagonism are unknown. Two small phase II trials have shown a response rate to Arzoxifene of >30% among women with receptor positive metastatic disease. We propose to perform a multi-institutional trial of Arzoxifene in women with advanced or recurrent endometrial adenocarcinoma and to combine these clinical investigations with laboratory-based studies to identify potential mechanisms of action of this SERM. Hypothesis and Specific Aims: Our aims are three fold:
Significance: Completion of the clinical trial will substantiate the effectiveness of Arzoxifene as a therapeutic agent. Laboratory correlates performed in conjunction with this trial will provide insight into the molecular mechanism of antagonism of Arzoxifene in endometrial carcinoma. Project 2 Background: Our studies are based on the observation that obesity is a strong risk factor for the development of endometrial cancer in post-menopausal women. Although part of this increased risk appears to be linked with hyper-estrogenization associated with obesity, it is our hypothesis that hyper-insulinemia also contributes to the development of endometrial cancer. Drugs that suppress insulin resistance, such as the thiazolidinedione insulin sensitizers, may have activity in suppressing abnormal endometrial proliferation in obese post-menopausal women. We speculate that insulin sensitizer therapy may constitute a novel, safe effective form of chemopreventive therapy for this disease. Hypotheses and Specific Aims: Our approach involves three distinct experimental modalities.
Significance: Increased endometrial cancer risk most closely associated with obesity, but there is also strong evidence that obesity increases risk of post-menopausal breast cancer. This proposal will examine the contribution of obesity and insulin resistance to the increased risk of estrogen associated cancers, using endometrial cancer as a model. Certainly the ability to decrease breast cancer risk, as well as endometrial cancer risk, with insulin sensitizers would have a major public health impact. This study also proposes a novel chemoprevention strategy. Rather than using an agent that focuses on prevention of a single cancer, we propose to treat an underlying metabolic syndrome that may decrease the risk of several hormonally associated cancers. In addition, use of an insulin-sensitizing agent may have a more favorable risk: benefit ratio than other options, including aromatase inhibitors or selective estrogen receptor modulators. Project 3 Background: Methylation of CpG islands is an epigenetic mechanism of regulating gene expression that has been described in great detail for colon cancer. Methylation is an important mechanism of gene silencing that can suppress the expression of tumor suppressor genes and other growth regulatory genes important in neoplasia. We hypothesize that methylation is an important mechanism of gene silencing in a subset of endometrial cancers. Endometrial cancer is a complex, heterogeneous disease that can be broadly classified into two groups according to histopathological, molecular, and clinical characteristics. Type 1 endometrial cancer is generally associated with estrogen exposure and is less clinically less aggressive. Type 2 cancers are not dependent on estrogen and are associated with local recurrence, distant metastasis, and shortened survival. There are numerous patient populations at risk for developing endometrial cancer. High-risk characteristics include endometrial hyperplasia, anovulatory cycle, tamoxifen use, obesity with insulin-resistance, and exposure to environmental estrogens. Hypotheses and Specific Aims: For the first three specific aims, a large panel of markers known to be methylated in various cancers will be used to generate molecular fingerprints of endometrial tissues.
Significance: The main goal of the proposed project is to evaluate CpG island methylation as a mechanism of gene silencing in endometrial cancer. As a result of the experiments proposed for this project, we expect to use methylation profiling as unique molecular fingerprints of the different types of endometrial cancer. These methylation profiles will then be tested as possible prognostic indicators in women at risk for the development of endometrial cancer. Groups at risk for the development of endometrial cancer include women with endometrial hyperplasia, women treated with tamoxifen for breast cancer, and women with anovulatory cycles. The methylation profiles tested in the cancers will be applied to each of these high-risk groups. Finally, we will use well-established techniques to clone and identify genes differentially methylated in endometrial cancer. Identification of such genes with differentiated methylation patterns will hopefully provide molecular clues as to the fundamental differences between type 1 endometrial cancers (less aggressive) and type 2 endometrial cancer (more aggressive). Project 4 Background: Estrogen exposure is well documented to be important in the pathogenesis of endometrial cancer. We hypothesize that normal growth control pathways induced by estrogen are dysregulated in endometrial hyperplasia and cancer. By identifying genes that are dysregulated, we can 1) further our understanding of the step-wise progression in endometrial carcinogenesis and 2) identify genes that can be used as surrogate biomarkers of endometrial cancer risk. Identification of these tissue biomarkers is crucial for the successful design of chemoprevention trials. In addition, these biomarkers potentially can be used clinically as tissue indicators of risk in high-risk groups. High-risk groups include women using SERMs such as tamoxifen, women with HNPCC, and women with obesity and type 2 diabetes. We have recently analyzed gene expression changes in post-menopausal endometrium exposed to different estrogen preparation using DNA microchip array analysis and real-time quantitative PCR (Q-PCR). The array analysis identified several hundred genes that are regulated by estrogen. From this large set of estrogen regulated genes, and additional genes selected for their role in the development of endometrial hyperplasia, a set of 33 transcripts of identified that are involved in proliferation of the endometrium. Hypothesis and Specific Aims: We hypothesize that normal growth control pathways induced by estrogen are dysregulated in endometrial hyperplasia and cancer. Our approach will be to make quantitative measurements of mRNA levels of this set of potential biomarkers in endometrial biopsy samples in different states of proliferation: normal, hyperplasia, and cancer.
Significance: The overall goal of this project is to identify and validate an essemble of biomarkers whose expression in the endometrium changes during the progression from normal quiescent to normal proliferative through hyperplastic states into carcinoma. A combination of qualitative and quantitative measurements will be made to identify candidate biomarkers. Such a genetic essemble will be useful for identifying women at risk for endometrial cancer and for providing molecular indicators of prognosis. ADMINISTRATIVE CORE The overall goal of the Administrative Core is the effective management of all activities relating to the SPORE. The Administrative Core will actively work to communicate and disseminate information to both SPORE investigators and to external constituencies. Dr. Thomas Burke, Principal Investigator of the Administrative Core and Overall Project, will direct these activities. Specific aims are to:
PATHOLOGY CORE The goal of the Pathology Core is to provide frozen tissue, paraffin-embedded tissue, and histopathological expertise related to the specific needs for the research projects within this SPORE program. To achieve this goal, the Pathology Core proposed the following specific aims:
BIOMARKER CORE The Biomarker Core will provide a centralized resource for the rapid and high throughput quantitation of transcripts using fluorescent real-time reverse transcriptase-coupled quantitative PCR (Q-PCR). The use of the Biomarker Core will serve fundamental purposes:
The following specific aims represent interactions between projects in the SPORE and the Biomarker Core:
BIOSTATISTICS & DATA MANAGEMENT CORE The Biostatistics and Data Management Core will serve the multiple needs for the planning and conduct of the SPORE’s translational research. This resource will be used for hypothesis refinement, experimental design, data management, quality control, result analysis and information presentation of results, and will function across all projects of the SPORE. Data from SPORE clinical trials and laboratory projects will be entered into a customized database application developed specifically for the SPORE. This computerized database will facilitate continuous monitoring of clinical trial results and will allow for automated data audits. Thus, from inception to reporting, translational experiments will benefit from SPORE resources that will be used to augment existing M.D. Anderson biostatistics resources. The specific aims of the Biostatistics and Data Management Core are:
DEVELOPMENTAL RESEARCH PROGRAM The overall aim of the Developmental Research Program is to provide initial funding to support innovative translational studies and exploratory research in gynecologic oncology. The support of translational research projects that can generate clinically testable hypotheses aimed at reducing the incidence of uterine cancer or leading to improved therapeutic outcomes or quality of life for gynecologic cancer patients will be emphasized. Pre-proposals in the form of project abstracts (1/2 – 1 page) will be solicited by the Program and applicants of responsive abstracts invited to submit Pilot Project proposals to the program. Proposals will follow an abbreviated R01 research grant format and be up to 5 pages in length. The Program Directors in conjunction with the Executive Committee of the SPORE will help investigators submitting proposals formulate relevant translational research aims and plans, as many investigators may not have previous expertise in this area. This process will therefore be a major educational activity that is anticipated to further stimulate translational research in gynecologic oncology and encourage the participation of both basic researchers and clinicians in translational research. Competing proposals will be evaluated and ranked by the SPORE Executive Committee. Projects will be funded for 1 year with the possibility of renewal for an additional year. It is anticipated that the Program will fund 2 pilot projects each year. All projects will be reviewed at the end of their first year with written progress reports and oral presentations at the SPORE annual retreat. CAREER DEVELOPMENT PROGRAM The goal of the Career Development Program is to develop highly trained investigators dedicated to translational studies in human uterine cancer. The program will: Recruit and train physician and basic science postdoctoral fellows to become highly skilled translational investigators in the field of uterine cancer;
The unique educational environment that exists at M.D. Anderson Cancer Center, the University of Texas Health Science Center, and other institutions of the Texas Medical Center will aid in achieving these goals. Solicitations will be made for qualified candidates from M.D. Anderson Cancer Center, including physicians in our Gynecologic Oncology and Pathology fellowship programs, basic science graduates of our Graduate School of Biomedical Sciences, and residents/fellows in the Department of Obstetrics, Gynecology, and Reproductive Sciences at the U.T. Houston Medical School, as well as M.D. and Ph.D. candidates identified by national advertisements. The SPORE Executive Committee will interview candidates, make the final selection of fellows, and approve the placement of the trainee in a research laboratory, making this decision based upon the interests and research experience of the trainee and the availability of suitable resources. Minorities and women will be encouraged to apply by several specific mechanisms. In additional to research training via their individual projects, fellows will participate in activities designed to provide an overview of current knowledge, problems, and opportunities in uterine cancer research, state-of-the-art techniques and approaches for translational research, career development activities such as grant preparation and seminar presentations, and the opportunities to interact with established senior investigators in human uterine cancer research. Some of these enrichment activities will be open to the entire Texas Medical Center community to further increase knowledge and interest in uterine cancer issues within the wider biomedical community. M.D. Anderson Gynecologic SPORE for Uterine Cancer List of Investigators Diane C. Bodurka, M.D. Russell R. Broaddus, M.D., Ph.D. Thomas W. Burke, M.D. Peter J.A. Davies, M.D., Ph.D. Michele Follen, M.D., Ph.D. David M. Gershenson, M.D. Leslie I. Gold, Ph.D. Jean-Pierre Issa, M.D. Charles Levenback, M.D. David S. Loose, Ph.D. Karen H. Lu, M.D. Peter Mueller, Ph.D. Lois Ramondetta, M.D. Gregory L. Shipley, Ph.D. George M. Stancel, Ph.D. Cheryl L. Walker, Ph.D. Judith K. Wolf, M.D.
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