SPOREs : Organ-Specific SPORE Programs : Gynecologic (GYN)

The University of Texas M. D. Anderson Cancer Center SPORE in Uterine Cancers

Karen H. Lu, M.D., Principal Investigator
Professor
Department of Gynecologic Oncology
M. D. Anderson Cancer Center
University of Texas M.D. Anderson Cancer Center
1155 Pressler Street, Unit 1362
Houston, TX 77030
Tel: (713) 795-8902
Fax: (713) 792-7586

For more information on this specific SPORE's institution, please visit: http://www.mdanderson.org/departments/spores/display.cfm?id=eaa7e8fe-779b-11d4-aec300508bdcce3a&method=displayfull

Purpose and Intent

Uterine (endometrial) cancer is the most common gynecologic malignancy and the fourth most common cancer in women. The American Cancer Society estimates that in 2008, 40,100 women, an average of 110 a day, will be diagnosed with uterine cancer in the United States – and 7,470 women, an average of 20 women each day, will die from this disease.

Despite being the fourth most common cancer in women, there is very little public awareness about uterine cancer, and research funding has traditionally lagged behind that for other cancers. Uterine cancer is highly curable if caught early.

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. Significantly, there has been no decrease in the incidence or mortality of this cancer over the last 15 years.

The 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:

1. Decipher the fundamental molecular differences between Type 1 and Type 2 endometrial cancers.
2. Provide a panel of molecular markers that will be useful in endometrial cancer prognosis and in identifying patients at risk for developing the malignancy.
3. Dissect the molecular pathways involved in estrogen and progesterone mediated growth regulation of the uterine endometrium.
4. Promote novel strategies in the chemoprevention of endometrial cancer.
5. Target intracellular signaling pathways known to be important for endometrial carcinoma growth for the novel therapy of advanced/recurrent disease.

PROJECT 1: ENDOMETRIAL CARCINOMA: DEVELOPMENT OF NOVEL THERAPEUTIC AGENTS TARGETING SIGNAL TRANSDUCTION

Principal Investigators: Thomas W. Burke, M.D.; Cheryl L. Walker, Ph.D.; Judith Wolf, M.D. Co-Investigators: Leslie Gold, Ph.D.; Lois Ramondetta, M.D.

Background: No effective hormonal therapy, cytotoxic chemotherapy, or radiation therapy for the treatment of advanced/recurrent endometrial carcinoma currently exists. It is therefore the purpose of this project to target intracellular signaling pathways known to be important for endometrial carcinoma growth for the novel therapy of advanced/recurrent endometrial cancer.

Hypothesis and Specific Aims: Our aims are three fold:

Aim 1: Evaluation of the clinical efficacy of therapeutic agents that target signal transduction defects in endometrial carcinoma. In this aim we propose to examine mTOR as a therapeutic target for advanced/recurrent endometrial cancer. This aim will include a clinical trial to evaluate the effect of blocking mTOR activity in advanced/recurrent endometrial cancer with the mTOR inhibitor, RAD001. Studies to identify molecular markers that can predict response to this therapy are included in this aim as well.

Aim 2: Identification of biomarkers and laboratory correlates that can be used to predict or enhance the efficacy of therapeutic agents that target PI3K signaling. In this aim we will conduct preclinical studies to evaluate the efficacy of AKT and mTOR inhibitors for endometrial carcinoma.

Aim 3: Development of new in vitro assays that can be used to study therapeutic agents that impact PI3K signaling in endometrial cells and mechanisms by which stromal-epithelial cell interactions may influence response to therapy.

Significance: Completion of the clinical trial will substantiate the effectiveness of mTOR as a therapeutic agent. Laboratory correlates performed in conjunction with this trial will provide insight into the molecular mechanism of mTOR in endometrial carcinoma.

PROJECT 2: A NOVEL ENDOMETRIAL CANCER CHEMOPREVENTION STRATEGY FOR OBESE, INSULIN-RESISTANT WOMEN – AN AT-RISK POPULATION

Principal Investigators: Karen H. Lu, M.D.; Peter J.A. Davies, M.D., Ph.D.
Co-Investigators: Andrea Milbourne, M.D.

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.

Aim 1: To test the hypothesis that obesity and insulin resistance increase estrogen-dependent proliferation in the endometrium on animal models of obesity and insulin resistance. In addition, the ability of insulin sensitizers to reverse this effect will be studied. Specific genes involved in estrogen-regulated proliferation pathways will be examined by quantitative PCR, including hormone receptors and co-activators and genes involved in the Wnt pathway, IGF pathway, TGF-β and retinoid pathway.

Aim 2: To identify novel genes and pathways associated with insulin resistance and estrogenization, and to identify relevant and specific biomarkers that are modulated by normalization of insulin resistance. Expression profiling with cDNA microarrays will be used to explore the effects of obesity and insulin resistance on both estrogen-dependent and estrogen-independent endometrial gene expression. In addition, specific biomarkers of the endometrium that are modulated by insulin-sensitizers will be identified.

Aim 3: To assess the ability of an insulin-sensitizing agent to modulate surrogate endometrial biomarkers in a post-menopausal cohort of obese, insulin resistant women. The post-menopausal cohort includes obese women (body mass index > 30 kg/m²) who demonstrate insulin resistance based on an oral glucose tolerance test, but who do not fulfill criteria for Type II Diabetes. We hypothesize that metformin, an insulin-sensitizing agent, will modulate relevant endometrial proliferation biomarkers. In pre- and post-treatment endometrial biopsies, we will assess expression levels of genes involved in estrogen-regulated growth pathways, specific biomarkers as defined in Aim 2 and histologic and proliferation markers. As secondary endpoints, we will establish a point estimate of the baseline frequency of endometrial abnormalities in this cohort and we will determine changes in serum levels of estradiol, estrone, testosterone, DHEA-S and SHBG in obese, post-menopausal women taking metformin.

Significance: There is an increased endometrial cancer risk 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: METHYLATION PROFILING OF ENDOMETRIAL CANCER

Principal Investigators: Russell R. Broaddus, M.D., Ph.D.; David S. Loose, Ph.D.
Co-Investigator: Jean-Pierre Issa, M.D.

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.

Aim 1 will examine CpG island methylation in Type 1 and Type 2 endometrial cancers to support the hypothesis that methylation profiling can provide molecular clues to the differences between Type 1 and Type 2 cancers.

Aim 2 will use methylation profiling of endometrial hyperplasia, a precursor to endometrial cancer, to determine if CpG island methylation is an early event.

Aim 3 will determine if methylation profiling can accurately identify “at-risk” endometrium.

Aim 4 will determine, using laboratory models, if epigenetic manipulation affects endometrial cancer cell invasion.

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: MOLECULAR PROGRESSION OF ENDOMETRIAL CANCER

Principal Investigators: David S. Loose, Ph.D.; Karen H. Lu, M.D.
Co-Investigators: Gregory L. Shipley, Ph.D.; George M. Stancel, Ph.D.

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 (Lynch syndrome), 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.

Aim 1: Quantitate the set of 33 candidate biomarkers in women treated with conjugated estrogens, normal secretory and normal proliferative pre-menopausal endometrium, hyperplastic endometrium both with and without nearby cancer, and type I and type 2 endometrial cancer. Using laser capture microdissection, we will focus on the precancerous lesion endometrial intraepithelial neoplasia (EIN) and assess transcript levels in EIN and in normal adjacent regions.

Aim 2: High density microarrays will be screened to identify new genes whose expression is altered in hyperplasia and cancer compared to normal endometrium. Genes that are identified by the microchip analysis will be validated by Q-PCR. The combination of aims 1 and 2 will identify a set of “abnormal proliferation” biomarker transcripts.

Aim 3: We will test the ability of the biomarkers to predict changes in proliferation by quantitating transcript levels in women treated with progestins for atypical hyperplasia. We hypothesize that biomarkers that are elevated in abnormal proliferation will be reduced by progestin treatment. Biomarkers will also be quantitated in endometrial biopsies from women with HNPCC (Lynch syndrome), a group at risk for developing endometrial cancer, who have been treated with either oral contraceptives or depoProvera. This panel of biomarkers may be extended for use in the future analysis of endometrial effects in high risk cohorts.

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

Directors: Karen H. Lu, M.D.; Russell R. Broaddus, M.D., Ph.D.; Thomas W. Burke, M.D.; George M. Stancel, Ph.D.
Administrative Contact: Jennifer L. Stanley

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. Specific aims are to:

• Plan and oversee all SPORE activities, including monitoring of timelines for each SPORE project
• Provide administrative support for the projects, cores, and Developmental Research and Career Development Programs
• Communicate and consult with NCI Organ Systems Branch staff to assure the accurate and timely submission of all required reports and publications and to promptly notify the project officer of important events that affect the management of the SPORE
• Coordinate quality assurance activities, including data quality controls, through the Executive Committee and Advisory Committee of Internal and External Advisors with support from the Biostatistics, Biomarkers, and Pathology Cores
• Oversee all fiscal and budgetary issues
• Convene and provide administrative support for meetings of the Executive and Advisory Committees
• Assure compliance with all general, governmental, NCI, and institutional regulations and requirements
• Support policies for recruitment of women and minorities as both investigators and participants in clinical trials
• Coordinate research projects with other Gynecologic Cancer SPOREs, the Gynecologic Oncology Group (GOG), and SPOREs in other disease sites through distribution of materials, electronic communications, progress reports, and participation in joint meetings.
• Expand our existing website focused on translational research activities in uterine malignancies to serve as a communication center regarding meetings, invited speakers, and manuscripts.
• Assist in preparation of all reports, manuscripts, and abstracts resulting from SPORE activities.
• Provide management and coordinate the overall information systems support for the SPORE, to include an integrated and centralized database management and quality control application.

PATHOLOGY CORE

Directors: Russell R. Broaddus, M.D., Ph.D.; Karen H. Lu, M.D.

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:

Aim 1: To maintain a frozen and paraffin-embedded repository of endometrial cancers, hyperplasias and normal endometrial samples.

Aim 2: To provide pathological review for all clinical specimens utilized in the SPORE projects and to provide histopathological technical services as necessary. Such technical services include immunohistochemistry, in situ hybridization and microdissection of tissue sections.

Aim 3: To establish a blood/urine/ascites fluid repository from patients undergoing hysterectomy for endometrial cancer and endometrial hyperplasia. These fluids will provide the resources for the systematic testing of putative prognostic and diagnostic markers isolated from endometrial tissues. Furthermore, using the novel technique of phage display, novel tumor markers can be discovered from the serum or ascites fluid of endometrial cancer patients.

Aim 4: To construct various endometrial tissue arrays using the Beecher Instruments microarray device. Such tissue arrays will provide for more rapid immunohistochemical analysis of protein expression.

Aim 5: To create a SPORE database for all samples collected at M. D. Anderson Cancer Center. The database will provide for a virtual tissue repository that can be electronically shared with all SPORE investigators

BIOMARKER CORE

Director: David S. Loose, Ph.D.

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:

Quantitative assessment of gene expression at the mRNA level for known genes that are involved in proliferation and implicated in cancer progression, and genes that are known markers for estrogen action in either normal or malignant endometrium.

Quantitative validation of the expression of genes that are initially identified in screening high-density microarrays. This is a critical adjunct to the microarray screening and will require development of a significant number of new Q-PCR assays.

BIOSTATISTICS & DATA MANAGEMENT CORE

Director: Peter Mueller, Ph.D.

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:

1. To provide guidance in the design and conduct of clinical trials and other experiments arising from the ongoing research of the SPORE.
2. To provide innovative statistical modeling, simulation techniques, and data analyses needed by the Projects, Developmental Projects and other Cores to achieve their Specific Aims.
3. To ensure that the results of all Projects are based on well-designed experiments and are appropriately interpreted.

DEVELOPMENTAL RESEARCH PROGRAM

Directors: Cheryl L. Walker, Ph.D.; Peter J.A. Davies, M.D., Ph.D.; Charles Levenback, M.D.

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 five 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 one year with the possibility of renewal for an additional year. It is anticipated that the program will fund two 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.

Developmental Research Awards
Year, Recipient

2003-2004

Jennifer K. Richer, PhD and
Meenakshi Singh, MD
University of Colorado Health Sciences Center
Alterations in co-activator levels in endometrial cancer

Richard R. Behringer, PhD
UT M. D. Anderson Cancer Center
Transgenic mice for endometrium-specific modifications

2004-2005

Mark T. Bedford, PhD
UT M. D. Anderson Cancer Center
Arginine methyltransferases as novel therapeutic targets for endometrial carcinoma

Diego H. Castrillon, MD, PhD
UT Southwestern
Genetic mechanisms of endometrial carcinogenesis

Shi-Wen Jiang, MD and
Sean Dowdy, MD
Mayo Clinic
Preclinical studies on epigenetic modification reagents for endometrial cancer treatment

2005-2006

Donghai Dai, MD, PhD
University of New Mexico Health Science Center
Synergistic anti-cancer effect of paclitaxel and amifostine in poor outcome endometrial cancer

2006-2007

Constance T. Albarracin, MD, PhD
UT M. D. Anderson Cancer Center
MicroRNA profiling to identify functional gene targets in endometrial carcinoma

2007-2008

Bo Rueda, PhD
Harvard Medical School
Delineating the unique gene expression features of the endometrial tumor initiating cell fraction

Jae-Wook Jeong, PhD
Baylor College of Medicine
The role of Mig-6 in the tumorigenesis of endometrial cancer

Anil K. Sood, MD and
Robert Coleman, MD
UT M. D. Anderson Cancer Center
EphA2 targeting for anti-vascular therapy of endometrial carcinoma

CAREER DEVELOPMENT PROGRAM

Directors: George M. Stancel, Ph.D., David M. Gershenson, M.D.

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.

Provide specific knowledge of research in uterine cancer that will have the ability of awardees to conduct innovative translational science that will directly impact on the understanding and treatment of this disease.

Redirect individuals who already have shown considerable scientific promise into uterine cancer research.

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.

Career Development Awards
Year, Recipient

2003-2004

Limin Gong, PhD
UT M. D. Anderson Cancer Center
Study of MR-1 in human endometrial cancer cells

Jubilee Brown, MD
UT M. D. Anderson Cancer Center
Analysis of racial and ethnic differences in endometrial cancers

2004-2005

Brian Slomovitz, MD
UT M. D. Anderson Cancer Center
Clinical and translational evaluation of mTOR inhibition for the treatment of endometrial carcinoma

Limin Gong, PhD
UT M. D. Anderson Cancer Center
Study of MR-1 in human endometrial cancer cells

2005-2006

Jennifer Richer, PhD
University of Colorado Health Sciences Center
ZEB1 in endometrial cancer

Salama A. Salama, PhD
UT Medical Branch
Catechol estrogens and estrogen-metabolizing genes in endometrial cancer

2006-2007

Jae-Wook Jeong, PhD
Baylor College of Medicine
The role of ERRFI1 in the tumorigenesis of endometrial cancer

Lei Deng, PhD
UT M. D. Anderson Cancer Center
EIG121 as a molecular switch for endometrial carcinoma differentiation

2007-2008

Jae-Wook Jeong, PhD
Baylor College of Medicine
The role of Mig-6 in the tumorigenesis of endometrial cancer

Jinping Li, MD, PhD
Mayo Clinic/Mercer University
Tumor promoting activity of human epididymis protein 4 (HE4) in endometrial cancer progression

Shannon Westin, MD
UT M. D. Anderson Cancer Center
Use of estrogen-regulated transcripts to predict response to intrauterine progesterone therapy in early endometrial disease

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