THE UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER SPORE IN OVARIAN CANCER
The overall goal of the University of Texas M. D. Anderson Cancer Center (MDACC) SPORE is to reduce the morbidity and mortality of ovarian cancer through innovative translational research in the detection and treatment of ovarian cancer based upon the genomics and biology of the disease.
Project 1: Early Detection of Epithelial Ovarian Cancer
Co-PIs: Robert C. Bast, Jr., M.D.
Karen Lu, M.D.
Background: The goal of Project 1 is to develop effective strategies for early detection of ovarian cancer in women at average risk for the disease. The possibility of screening is based on several biological assumptions: 1) that ovarian cancers generally arise from clones of cells; 2) that most metastatic disease arises from clinically detectable lesions isolated to the ovary; and 3) that there is a reasonable interval from the development of invasive cancer to conventional diagnosis of the disease. SPORE investigators have addressed each of these questions and demonstrated that most ovarian cancers are clonal and that there may be as much as 1.9 years from the initial growth of an ovarian cancer prior to its clinical detection.
One of the most promising approaches to early detection of this neoplasm is to use rising values of a serum marker such as CA 125 to prompt the performance of transvaginal sonography (TVS). Patients with abnormal TVS or a sufficiently rapid rise in CA 125 undergo exploratory surgery. If one is to pursue a two-stage strategy for early detection, the initial stage must be optimally sensitive. No single marker is likely to be adequately sensitive and multiple markers may be required to detect the full spectrum of ovarian cancers. Simple addition of multiple markers may increase sensitivity but generally decreases specificity, posing a particular problem in a disease with the prevalence of ovarian cancer.
We have found that alterations in gene expression in early-stage high-grade serous cancers resemble those in late-stage disease, consistent with the development of stage III/IV from stage I lesions. Given the prevalence of ovarian cancer among postmenopausal women, a diagnostic strategy must be moderately sensitive (>75%), but highly specific (>99.6%) to achieve a positive predictive value of 10%, i.e., 10 laparotomies for each case of ovarian cancer detected.
Specific Aims
Aim 1. To identify an optimally sensitive panel of known and novel markers for ovarian cancer that, in aggregate, detect >90% of early-stage cancers.
Aim 2. To develop and test statistical techniques which permit utilization of multiple markers over time to detect early ovarian cancer, increasing sensitivity without compromising specificity.
Aim 3. To conduct a screening trial in women at average risk to determine whether the CA 125 algorithm achieves a positive predictive value of 10% and to build a bank of serum and plasma specimens from the same volunteers over a period of years.
Project 2: Cell-Specific Targeting of Ovarian Cancer Vasculature
Co-PIs: Anil Sood, M.D.
Robert Coleman, M.D.
Robert Jaffe, M.D. (University of California, San Francisco)
Background: The progressive growth of primary ovarian cancer and metastasis is dependent on development of an adequate blood supply (angiogenesis). Vascular endothelial growth factor (VEGF) plays a critical role in angiogenesis and consequent ovarian cancer growth and progression. VEGF blockade has shown promise in human studies. The overall goal of this new SPORE Project is to develop new strategies for targeting blood vessels in ovarian cancers. Our preclinical results demonstrate that a novel approach (high-affinity VEGF decoy receptor, VEGF-Trap) for VEGF blockade is highly effective in combination with taxane chemotherapy. Recent evidence suggests that VEGF-Trap may be more potent than many other existing modalities for targeting VEGF.
Specific Aims
Aim 1. To conduct a phase I clinical trial of VEGF-Trap and docetaxel chemotherapy in patients with recurrent ovarian carcinoma. In addition to endothelial cells, blood vessels consist of perivascular cells such as pericytes, which are mesenchymal cells that wrap around the vessel tube. Several functions of pericytes relevant to angiogenesis have been proposed, including effects on endothelial survival, deposition of matrix, and maintenance of vessel integrity. Platelet-derived growth factor receptor (PDGF-R ) signaling is known to play a functionally significant role in pericyte development and recruitment by endothelial cells.
Aim 2. To determine the mechanisms by which pericytes provide a survival advantage for endothelial cells and assess the efficacy of combinatorial approaches for targeting both endothelial cells (VEGF-blockers) and pericytes (PDGF-blockers). Most chemotherapeutic agents are traditionally administered at maximum tolerated doses. However, recently, metronomic chemotherapy (frequent administration of chemotherapeutic agents at substantially lower doses with no prolonged drug-free breaks) has been utilized for targeting endothelial cells of the growing vasculature of a tumor. Our preliminary data suggest that metronomic chemotherapy alone and in combination with other antivascular approaches is highly effective.
Aim 3. To determine the efficacy of metronomic chemotherapy in combination with VEGF and PDGF blockers.
Project 3: Development of E1A Gene Therapy in Ovarian Cancer
Co-PIs: Mien-Chie Hung, Ph.D.
Naoto Ueno, M.D., Ph.D.
Judith Wolf, M.D.
Background
We have defined multiple antitumor activities associated with E1A gene expression and established an appropriate animal model to evaluate the anti-ovarian cancer activity of an E1A-liposome complex. A phase I study using E1A-liposome complex targeting of breast and ovarian cancers was completed and reported (J. Clin. Oncol. 19:3422-3433, 2001). Based on this experience, we initiated a phase II trial of intraperitoneal single-agent E1A gene therapy in patients with recurrent ovarian cancer in 2001. Because of the small number of patients who met the eligibility requirements, we terminated the phase II trial and initiated a new phase I/II trial that combines chemotherapy with E1A gene therapy and that has more appropriate eligibility requirements.
Specific Aims
Aim 1. To complete the phase I/II trial of E1A gene therapy combined with chemotherapy. Using a novel trial design, we will perform a randomized phase I/II trial in which one arm receives weekly i.v. paclitaxel (to establish a concurrent control group for a heterogeneous group of patients) and the other arm receives weekly i.v. paclitaxel with i.p. liposomal E1A gene therapy at different does levels. This study will define the toxicity, maximum tolerated dose (MTD), clinical response rate, and progression-free survival of weekly paclitaxel plus E1A-lipid complex treatment. Biopsies will be obtained to monitor therapy at the cellular level.
Aim 2. To develop an ovarian cancer-specific gene delivery system and expression vector. Two approaches will be used to improve systemic i.v. targeting of E1A gene therapy to treat ovarian cancer xenografts: 1) development of ovarian cancer-specific promoter elements and 2) conjugation of liposomes with targeting peptides, folate ligand, and anti-folate receptor antibodies.
Aim 3. To develop an effective combination of E1A gene therapy with other agents in a preclinical ovarian cancer model. Using ovarian cancer xenografts, we will test the efficacy and toxicity of E1A gene therapy in combination with cytotoxic drugs used to treat ovarian cancer patients as well as novel biologic agents (TNF and TRAIL). Preliminary data suggest that these agents may exert synergistic antitumor activity at subtoxic doses. The clinical data from Aim 1 and preclinical insights from Aims 2 and 3 can be combined in the future to design novel and potentially even more effective therapeutic strategies.
Project 4: Targeting the PI3K Pathway in Ovarian Cancer
Co-PIs: Gordon Mills, M.D., Ph.D.
John Kavanagh, M.D.
Background:
The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in many critical biological processes, including cellular proliferation, cell-cycle progression, viability, motility, invasion, neovascularization, and metastasis. Multiple components of the PI3K signaling cascade are aberrant in ovarian cancer at the DNA, RNA, and protein levels. These abnormalities in the PI3K pathway result in activation of the PI3K pathway in most ovarian cancers and likely contribute to patient outcome. We have demonstrated that treatment with the PI3K inhibitor LY294002 markedly decreases cell proliferation, production of neovascularizing factors, motility, and invasion of ovarian cancer cells in vitro and growth, production of neovascularizing factors, and neovascularization in xenografts in vivo.
Further, overexpression of PI3K or AKT renders ovarian cancer cells resistant to the effects of paclitaxel, a major drug used in the management of ovarian cancer. Inhibition of PI3K sensitizes ovarian cancer cells to paclitaxel both in vitro and in vivo. LY294002 is, however, not a good pharmacophore and will not move forward clinically. Our previous studies suggest that catalytic inhibitors of AKT, which is downstream from PI3K, have a prohibitively narrow therapeutic index. Recently, we have demonstrated that two novel PI3K pathway inhibitors-perifosine, which blocks the PH domain of AKT, and SF1126, which is a pharmacologically optimized prodrug for the PI3K inhibitor LY294002-inhibit proliferation, production of neovascularizing factors, motility, and invasion and sensitize cells to paclitaxel in vitro. Perifosine markedly decreases growth of ovarian cancer cells in an orthotopic transplantation model.
Specific Aims
Aim 1. To determine the efficacy of targeting PI3K with SF1126 and the PH domain of AKT with perifosine in ovarian cancer xenografts.
Aim 2. To develop and validate methods to determine biologically relevant effective dose and markers of early therapeutic response that can be translated to clinical trials.
Aim 3. To determine the efficacy of targeting ILK and PDK1 in ovarian cancer cells.
Aim 4. To assess biologic and clinical activity in molecular pharmacodynamic clinical trials targeting the PI3K pathway.
Project 5: Genome-based Marker and Therapy Development in Ovarian Cancer
Co-PIs: Joe W. Gray, Ph.D. (Lawrence Berkeley Laboratory, Berkeley, CA)
David Gershenson, M.D.
Rosemarie Schmandt, Ph.D.
Background
The overall goals of this Project are to develop strategies to identify ovarian cancer patients least likely to respond to modern platinum/taxane-based treatments and to develop therapeutic strategies to attack cancer cells in these patients. This will be accomplished in two steps.
Specific Aims
Aim 1. To develop and validate an accurate and clinically robust assay to identify patients that will survive less than 36 months after treatment with surgery plus platinum/taxane-based therapies.
Aim 2. To develop siRNA and/or small molecule inhibitors for genes in regions of amplification at 8q24, 11q13, and/or 20q11-q13 that cause reduced apoptotic surveillance when overexpressed.
CORES
Core A: Administrative Core
Director: David Gershenson, M.D.
CoDirector: Robert C. Bast, Jr., M.D.
Goals
The overall goal of the Administrative Core is to provide leadership and general administration for all activities related to the M. D. Anderson Ovarian SPORE.
Objectives
- To oversee all SPORE activities, including Projects and Core resources.
- To provide administrative support for the Developmental Research and Career Development Programs.
- To convene all meetings of the SPORE, including the Administrative Core, the Executive Committee, and scientific meetings.
- To convene all meetings of the Internal, External, and Advocate Advisory Committees.
- To coordinate data quality-control and quality-assurance issues in conjunction with the Biostatistics Core.
- To monitor and oversee all fiscal and budgetary issues.
- To interface closely with the other oversight committees related to ovarian cancer research at our institution, including the Gynecological Oncology Tumor Bank Oversight Committee, the Executive Committee of the Blanton-Davis Ovarian Cancer Research Program, and the Multidisciplinary Program Steering Committee.
- To coordinate research with other ovarian SPOREs and other SPOREs, by distributing materials, electronic communications, and progress reports.
- To communicate with the NCI Project Officer and other staff to prepare all required reports and publications. The NCI Project Officer will be promptly notified of important developments that affect the management of the SPORE either positively or negatively.
- To assure compliance with all general, governmental, and NCI regulations and requirements.
- To establish and implement policies for recruitment for women and minorities.
Core B: Biostatistics Core
Director: E. Neely Atkinson, Ph.D.
CoDirector: Keith Baggerly, Ph.D.
Goals
The goal of the Biostatistics Core is to provide statistical support for the Projects, assist in the design of new studies and projects, and work with the InterSPORE Bioinformatics Committee on the definition of common data elements related to the SPOREs and on the construction of a common Ovarian SPORE tissue data base.
Objectives
- To provide the statistics and data analysis required by the Projects and Cores to achieve their specific aims. The Core will provide expertise and computational facilities to perform the statistical analyses required by each Project.
- To assist in the design and implementation of new trials and studies arising from the ongoing research of the SPORE. As progress is made in each Project, new experiments and trials will be developed. The Biostatistics Core will lead the design of such proposed trials. If ongoing studies need to be modified, the Core will participate in the redesign to insure that the statistical properties of the trial are maintained.
- To provide guidance to the Projects and Cores in data management issues such as data entry and retrieval, quality assurance, security, and data backups. All the investigators involved in the SPORE have experience with the software required to enter, maintain, and retrieve the data produced by their Projects. As necessary, the Core will provide assistance in the data management of each project. The Core will provide expertise in the selection of software and in data design, audit, and backup.
- 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. Success of the SPORE depends upon a close cooperation among the Projects and Cores. The Biostatistics Core will facilitate the exchange of data and information between Projects. The Core will assist in electronic transfer and in the selection of data items and format to ensure data compatibility.
Core C: Pathology Core
Director: Russell Broaddus, M.D., Ph.D.
CoDirector: Jinsong Liu, M.D., Ph.D.
Goals
The individual research projects that make up this Ovarian Cancer SPORE application require the procurement, processing, and analysis of histopathological material from patients with ovarian cancer and benign ovarian diseases. The research projects have needs for frozen and formalin-fixed, paraffin-embedded samples of tumor and normal tissue. The Pathology Core augments the already established M. D. Anderson Cancer Center Gynecological Tumor Bank and the P30-sponsored M. D. Anderson Cancer Center Centralized Tissue Repository with supporting database and intranet access. The Core provides tissue acquisition by experienced gynecological pathologists to assure high-quality tissues for the investigators participating in this SPORE as well as investigators of other SPOREs. 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 in this SPORE.
Objectives
- To maintain a frozen and paraffin-embedded tissue repository of ovarian cancer, benign ovarian processes, and normal ovary. The primary tissue source is operative and biopsy specimens submitted to the Department of Pathology at M. D. Anderson Cancer Center. In addition, a subcontract with Duke University provides additional ovarian tissues, particularly early stage ovarian cancers.
- 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, creation of specific tissue microarray slides, and microdissection of tissue sections.
- To establish a blood/urine/ascites fluid repository from patients undergoing surgery for ovarian cancer and benign ovarian processes. These fluids provide the resources for the systemic testing of putative prognostic and diagnostic markers derived from tissue-based expression array and CGH experiments.
- To create and maintain a SPORE database for all samples collected at both M. D. Anderson Cancer Center and Duke University. This SPORE database is a virtual tissue repository that is electronically shared by all SPORE investigators.
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