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UNIVERSITY OF TEXAS, MD ANDERSON CANCER CENTER
PROJECT I
EARLY DETECTION OF OVARIAN CANCER
Principal Investigator(s): Robert C. Bast, Jr., M.D.; David Fishman, M.D.; David Smith; Ph.D.; Steven Skates, Ph.D.
Co-Investigator(s): Karen H. Lu, M.D.; Rosemary Schmandt, Ph.D.; Jinsong Liu, M.D., Ph.D.
Background: When ovarian cancer is detected in stage I, 90% of patients can be cured with currently available therapy. When disease has spread throughout the peritoneal cavity (stage III) or beyond (stage IV) the cure rate drops to 20% or less. At present approximately two thirds of patients are diagnosed in stage III or IV and only 25% in Stage I. Detection of preclinical disease at an earlier stage might impact on survival. The success of any strategy for early detection depends critically upon the biology of ovarian cancer. Several factors are required: 1) most ovarian cancers must be clonal; 2) most advanced stage disease must actually develop from clinically detectable stage I lesions; and 3) the interval prior to metastasis must be sufficiently long to permit screening at annual or semiannual intervals. Given the prevalence of ovarian cancer in our population, any screening strategy must have a sensitivity of >75% and a specificity of 99.6% to achieve a positive predictive value of 10%, i.e., 10 operations for each ovarian cancer detected. Two screening strategies have been evaluated: ultrasonography and the use of serum markers such as CA 125. In studies published to date, some 73,000 women have been screened with ultrasound. Of the ovarian cancers detected, 73% have been in stage I, but the positive predictive value overall has been 5.6% ranging from 1.5% to 9.9% in different studies. A single determination of CA125 is not sufficiently specific or sensitive to provide an adequate screen. An algorithm has, however, been developed that considers the trend of multiple CA125 values over time. When used to trigger transvaginal sonography (TVS), a positive predictive value of 20% has been achieved in a randomized pilot study of 10,000 women in the United Kingdom. CA125 is expressed in only 80% ovarian cancers, limiting its sensitivity to detect all cases. Use of multiple serum markers might increase sensitivity, provided that specificity were maintained. Both algorithms over time and neural networks might contribute to optimizing sensitivity and specificity using multiple markers.
Hypotheses and Specific Aims: Our aims are three-fold. Aim 1 will identify novel markers for ovarian cancer using expression arrays. We will examine the possibility that the majority of genes upregulated in stage I ovarian cancer will also be upregulated in stage III ovarian cancer. We will also test the hypothesis that upregulation of oncogenes and downregulation of tumor suppressor genes will produce different alterations of gene expression in immortalized ovarian and breast epithelial cells. Genes that are selectively upregulated in transfected ovarian epithelial cells, in stage I ovarian cancers and in stage III ovarian cancers will be evaluated as markers. Aim 2 will develop statistical techniques that permit utilization of multiple markers monitored over time to detect early stage ovarian cancer. We propose that use of multiple markers over time can provide a more sensitive and no less specific test for ovarian cancer than the currently available CA 125 algorithm that is based on a single marker. Both previously characterized markers (CA 125II, CA 15-3, CA 72.3, CA 19-9, OVX-1, M-CSF, LPA and proteases) and novel markers (Aim 1 and markers to emerge from collaborations with Millennium Predictive Medicine) will be studied. We will evaluate a multivariate, longitudinal approach using artificial neural networks and hierarchical longitudinal change point methods. Specific Aim 3 will evaluate the CA 125 algorithm for ovarian cancer. In a single arm trial, we will test the hypothesis that the trend of CA 125 values over time can estimate the risk of ovarian cancer with a specificity of 98% and that the addition of TVS will further improve specificity. The CA 125 algorithm will be used to estimate the risk of ovarian cancer. A sufficiently high risk will prompt the performance of TVS. Serum and plasma specimens obtained in this trial will aid in evaluating the specificity of novel markers in Aim 1 and of multiple markers in Aim 2.
Significance: Early detection of ovarian cancer could impact substantially on mortality of this disease. Trials currently underway to evaluate TVS, CA 125 or the CA125 algorithm followed by TVS may show promise, but not optimize survival nor detect all women with early stage disease. Markers and methods developed in this project could provide the next generation of clinical trials for early detection of ovarian cancer.
PROJECT 2
ANTI-ANGIOGENESIS THERAPY OF HUMAN OVARIAN CANCER
Principal Investigator(s): Isaiah Fidler, DVM, Ph.D.
Co-Investigator(s): Judith Wolf, M.D.; Dominic Fan, M.D.; Elvio Silva, M.D.
Background: The progressive growth and spread of ovarian carcinoma is dependent in part on the formation and maintenance of adequate blood supply, ie., angiogenesis. We found that the expression of genes that regulate distinct steps in the process of angiogenesis correlates with the pattern and progressive growth of human ovarian carcinoma cells implanted into the peritoneal cavity of athymic nude mice: tumorigenicity correlated with expression of basic fibroblast growth factor (bFGF) and the production of ascites was directly correlated with expression of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), whereas progressive growth (and death of mice) was directly correlated with expression of interleukin-8 (IL-8).
Overall Guiding- Hypotheses and Specific Aims: The current results suggest two interdependent hypotheses: (i) the expression of angiogenesis-regulating genes in primary human ovarian cancer predicts the pattern of the disease and its clinical outcome; and (ii) targeting the IL-8 gene which may enhance ovarian cancer growth and angiogenesis could offer new approaches to the treatment of ovarian cancer. The specific aims include the following: (1) to determine whether the expression of angiogenesis-related genes in primary ovarian cancers predicts disease pattern and clinical outcome; (2) to determine whether the expression of IL-8 is essential for the progressive growth of human ovarian cancer cells; (3) to determine whether the organ microenvironment (hypoxia, acidosis) can regulate the expression of IL-8 in human ovarian cancer cells; and (4) to determine whether inhibition of IL-8 expression by interferon-beta (IFN-b) can inhibit angiogenesis and progressive (intraperitoneal) growth of human ovarian cancer.
Significance: The proposed research will shed new light on the process of angiogenesis (with emphasis on the role of IL-8) which is crucial for the progressive growth of human ovarian cancer. A better understanding of the role of IL-8 in the progression of human ovarian cancer and how IL-8 expression is regulated will allow the design of new therapeutic approaches to downregulate the expression of IL-8 and, hence, inhibit tumor cell growth and angiogenesis initially in orthotopic models and later in the clinic.
PROJECT 3
E1A GENE THERAPY IN OVARIAN CANCER
Principal Investigator(s): Mien-Chie Hung, Ph.D.; Naoto Ueno, Ph.D.
Co-Investigator(s): David Gershenson, M.D.; Leaf Huang, Ph.D.; Duen-Hwa Yan, Ph.D.; Keishi Makino, M.D., Ph.D.
Ovarian cancer is one of the major causes of death for women in the United States. Overexpression of the HER- 2/neu oncogene was reported to correlate with poor survival for ovarian cancer patients, enhance metastatic potential of human cancer cells and induce resistance to certain chemotherapeutic agents such as taxol (paclitaxel). Therefore, HER- 2/neu oncogene is an excellent target for development of novel anti-cancer agent for the HER- 2/neu -overexpressing cancer cells. Our experimental results indicate that adenovirus type 5, E1A, a transcriptional modulator, represses HER- 2/neu transcription in HER- 2/neu -overexpressing cancer cells; and that E1A-liposome complex inhibits tumor development in an ovarian cancer animal model. We, therefore, hypothesize that E1A, through repression of HER-2/neu, may function as a tumor suppressor for HER-2/neu- overexpressing ovarian cancer cells. Based on a series of preclinical data that derives this hypothesis, a phase I clinical trial entitled "Phase I Study of E1A Gene Therapy for Patients with Metastatic Breast or Epithelial Ovarian Cancer that Overexpresses HER-2/neu" has recently been completed. The results are encouraging and suggest feasibility of the E1A gene therapy for further clinical trials. The long-term goal of this proposal is to develop E1A gene therapy as an effective therapeutic approach for ovarian cancer. The targets in this proposal are to explore other anti-tumor activities associated with E1A and to understand its mechanisms, to develop novel approaches for targeting HER-2/neu-overexpressing ovarian cancer cells, and to complete phase II clinical trial using E1A/liposome treatment for HER-2/neu-overexpressing ovarian cancer patients. The Specific Aims of the proposal are described as following:
Specific Aim 1: E1A tumor suppressor function in ovarian cancer cells
Specific Aim 2: Mechanism of E1A tumor suppression function in ovarian cancer cells
Specific Aim 3: E1A-mediated chemo-sensitization in HER-2/neu-overexpressing ovarian cancer cells
Specific Aim 4: Development of E1A gene expression system specifically targeting HER-s/neu-overexpressing ovarian cancer cells using HER-2/neu antisense iron-responsive element
Specific Aim 5: E1A phase II clinical trials for Her-2/neu-overexpression ovarian cancer patients
PROJECT 4
ROLE OF THE PHOSPHATIDYINOSITOL SIGNALING CASCADE IN OVARIAN TUMORIGENESIS, PROGNOSIS AND THERAPY
Principal Investigator(s): Gordon Mills, M.D., Ph.D.; Joe W. Gray, Ph.D.; John Kavanagh, M.D.; Robert B. Jaffe, M.D.
Co-Investigator(s): Yiling Lu, M.D.
Background: Phosphatidylinositol 3'kinase (PI3K), plays a central role in cellular proliferation, neovascularization, invasiveness, viability, and senescence. PI3K and the MMAC1 (aka PTEN) tumor suppressor gene identified at MD Anderson Cancer Center phosphorylate and dephosphorylate the same 3'hydroxyl site of the inositol ring of membrane phosphatidylinositols (PtdIns).
Preliminary Data: We have demonstrated that the p110a catalytic subunit of PI3K, located at 3q26.3, is frequently genomically amplified in serous epithelial ovarian cancers. p110a mRNA, protein and PI3K enzyme activity are also increased in ovarian cancer cells. MMAC1 is frequently mutated in endometrioid ovarian epithelial cancers. These observations implicate the P13K signaling pathway in ovarian tumorigenesis. Treatment of cells with amplified P13K or mutant MMAC1 with specific P13K inhibitors markedly decreases cell proliferation and leads to apoptosis and anoikis. Further, reintroduction of MMAC1 into cells lacking, MMAC1 decreases cell proliferation and inducing, apoptosis and anoikis. LY294002 also decreases the growth of human ovarian cancer cells with amplified p110a in nude mice.
Rationale: Our preliminary data indicate that the P13K signaling cascade is critical to ovarian epithelial tumorigenesis and potentially invasion and metastases.
Hypothesis: That amplification and mutation of components of the P13K pathway is critically important for the initiation and progression of ovarian cancer. As a corollary, the P13K signaling cascade should be evaluated as a marker for prognosis and as a target for novel therapeutics aimed at ovarian cancer.
Specific Aim 1. What is the impact of amplification, mutation and activation of components of the P13K pathway on response to therapy or disease outcome?
Specific Aim 2. What is the role of amplification of the P13K pathway on production and action of TGFb, IL8, VEGF, and ligands for the HER2 family in ovarian cancer?
Specific Aim 3. Evaluate the P13K pathway as a target for therapy in ovarian cancer
Significance: The proposed studies will determine whether assessment of expression or functionality of components of the P13K pathway will predict patient outcome or drug sensitivity. The proposed studies will also determine the role of the P13K signaling pathway in the production and action of TGFb, IL8, VEGF, and ligands for the HER2 family in ovarian cancer studied in other projects in this SPORE. Finally, the proposed studies should determine whether the P13K signaling pathway is an appropriate target for drug development and identify lead compounds for preclinical and clinical development.
ADMINISTRATIVE CORE
Director(s): David Gershenson, M.D.; Robert Bast, Jr. M.D.
The Administrative Core will perform a number of functions essential to the success of this SPORE. The Core Director, Dr. David M. Gershenson, will facilitate the functions of all projects and cores. Dr. Robert C. Bast, Jr. and Dr. Gershenson will co-chair an Executive Committee comprised of all Project PI's, Co-PI's and Core Directors. The Executive Committee will meet every two weeks to review the scientific and fiscal status and progress of SPORE activities, to identify any problems or barriers, and to assure that all goals are met within realistic time and budget constraints. The Administrative Coordinator will work closely with the Director and Co-Director to schedule all meetings of the investigators and to ensure optimal communications with both internal and external investigators. The Director will hold weekly meetings with administrative personnel. All SPORE investigators will meet monthly to review research activities with the Internal Advisory Committee. The External Scientific Advisory Committee will meet for two days on an annual basis to evaluate progress. The specific responsibilities of the Administrative Core are (1) oversight of all activities of the SPORE, including Projects and Core Resources; (2) compliance with all general and NCI regulations and requirements; (3) communication and consultation with NCI governmental Project Officer and other staff, and preparation of all required reports and publications; (4) coordination of data quality control and quality assurance issues in conjunction with the Internal Advisory Committee and the Biostatistical Core; (5) maintenance of fiscal and budgetary functions; (6) convening of all necessary meetings, including the Executive Committee, the Internal and External Advisory Committees, monthly scientific meetings, quarterly research retreats, lectures, symposia; (7) administration of the Developmental Research Program; (8) administration of the Career Development Program; (9) establishment and monitoring of policies for recruitment of women and minorities to this program; and (10) coordination with other ovarian cancer SPORES and other organ site SPORES to promote and maintain communication and integration, including the distribution of materials, electronic communications, and evaluation of progress reports.
BIOSTATISTICS CORE
Director(s): E. Neely Atkinson, Ph.D.
The Biostatistics Core provides statistical expertise for planned and new studies and trials, supports the data management requirements of the projects and cores, and facilitates the exchange of data and information between the various projects.
The specific aims of the Biostatistics Core are:
1. to provide the statistics and data analysis required by the projects and cores to achieve their specific aims;
2. to assist in the design and implementation of new trials and studies arising from the ongoing research of the SPORE;
3. to provide guidance to the projects and cores in data management issues such as data entry and retrieval, quality assurance, security, and data backups;
4. to facilitate the exchange of information and data between the components of the SPORE by providing assistance in networking, email, data translation, and electronic file exchange.
PATHOLOGY CORE
Director(s): Elvio Silva, M.D.; Michael Deavers, M.D.
The Ovarian Pathology Facility at M.D. Anderson Cancer Center provides basic science and clinical investigators with human tissue for research projects from patients treated at M.D. Anderson for ovarian cancer. The core's functions include tissue collection and processing tissue storage, histopathologic review, specimen database management, and distribution of well- characterized specimens to project investigators. The main goal of SPORE is to provide adequate materials and services in support of the research projects included in the SPORE proposal; however, materials will be made available to SPORE investigators at other institutions whenever possible and to investigators outside the SPORE projects. The specific aims of the proposals are (1) to provide technical services and pathologic review of all clinical specimens used in the clinical and research projects outlined in the SPORE proposal, (2) to maintain a tissue repository of ovarian cancer specimens, (3) to retrieve paraffin-embedded tissue from M.D. Anderson archives and formalin-fixed and paraffin-embedded tissue from referring institutions and (4) to maintain on-line computerized database of pertinent data on each specimen and the patient from whom it was taken. Data and specimens will be made available to investigators at other SPORE sites. The core's computerized database contains data on specimen type, location, and clinical and pathologic findings for each specimen. Patient confidentiality is maintained by password protection.