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FRED HUTCHINSON CANCER RESEARCH CENTER
Overview
The Pacific Ovarian Cancer Research Consortium (POCRC) is a consortium of five non-profit organizations led by the Fred Hutchinson Cancer Research Center (FHCRC), including the University of Washington (UW), Swedish Medical Center (SMC), Pacific Northwest Research Institute (PNRI), and Cedars Sinai Medical Center (CSMC).
POCRC consists of a group of dedicated and enthusiastic scientists from a variety of disciplines who have come together to address the issues that we view as most critical in controlling ovarian cancer. We have identified five areas where opportunities exist for us to make a difference. The first is the identification and elucidation of the function of the genes that mediate chemo-resistence (Project 1). The second is the development of methods to create nucleic acid vaccines to be used eventually in ovarian cancer prevention (Project 2). The third is development of tools to estimate ovarian risk to support the screening and prevention trials that will be required to demonstrate the efficacy of interventions to reduce incidence and mortality from ovarian cancer (Project 3). The fourth is the development of statistical methods for selecting ovarian cancer markers to be included in a screening panel, and for tailoring the use of the panel to the individual woman to improve the efficacy and cost-effectiveness of screening (Project 4). The fifth is performance of a definitive study to demonstrate the efficacy or lack thereof of a facilitated group counseling intervention designed to improve advanced ovarian cancer patients' quality of life (Project 5).
The overall challenge of the program is to maintain a high level of interaction among scientists and rapidly communicate novel discoveries throughout the group. A Leadership Core will act as the foundation for scientific interaction, direction, mentoring, and program development. A Clinical Core will provide coordinated and comprehensive procedures for working with physicians to identify eligible women for enrollment in various research studies and activities in the SPORE and interact with the physicians and health care providers in Washington State to translate the research findings back to the community. A Specimen Core will collect, manage, and analyze tissue and blood products in support of the SPORE research projects.
Project 1
Genes Associated with Chemoresponsiveness in Ovarian Cancer
Principal Investigator(s): Nancy Kiviat, M.D., Marilyn Cornwell, Ph.D.
Co-Investigator(s): Michel Schummer, Ph.D.; Charles Drescher, M.D.
Chemoresistance is a significant obstacle to the successful treatment of ovarian cancer. Though standard chemotherapy regimens of cisplatin or carboplatin with paclitaxel are highly active and elicit substantial clinical response, resistance to these agents ultimately develops in nearly all patients. Molecular mechanisms of this drug resistance appear to involve multiple pathways modulated by many genes. The identification of genes that are expressed in correlation with response to chemotheraphy will lead to improved understanding of these mechanisms and more effective treatment. We propose to use high-density cDNA array-based hybridization (HDAH) and novel statistical techniques to identify genes that are differentially expressed in ovarian cancer patients sensitive to chemotherapy relative to patients resistant to the same regimen. In this work, we will ascertain the relative frequencies of over- and under-expression of genes known to be involved in chemoresistance. More importantly, this work will allow us to identify several dozen novel genes not previously associated with resistance to cisplatin and paclitaxel combination chemotherapy in ovarian cancer. The analysis of these novel genes will allow us to interpret their potential involvement in known resistance pathways. Though beyond the scope of this proposal, our findings will be useful in designing treatment strategies for overcoming resistance to chemotherapy and improving outcomes for patients suffering from ovarian cancer.
Project 2
Nucleic Acid Vaccines for the Chemoprevention of Ovarian Cancer
Principal Investigator(s): Ingegerd Hellstrom, M.D., Ph.D.; Mary L. Disis, M.D.;
Karl-Erik Hellstrom, M.D., Ph.D.
Co-Investigator(s): Nathalie Buonavista Scholler, M.D., Ph.D.
Ovarian cancer is highly lethal. Despite the fact that the majority of patients will be diagnosed with advanced stage disease, 60% of those patients will obtain a complete remission with a combination of chemotherapy and surgery. Unfortunately, these remissions will not be sustained and over 70% of patients will relapse and eventually die from progressive ovarian cancer. New treatments and prevention strategies are needed for ovarian cancer. Vaccines directed against ovarian cancer antigens provide therapeutic potential. Recent studies, by several groups including our own, have shown patients with ovarian cancer have an immune response to their tumors and some antigens that are immunogenic in ovarian cancer have been defined.
HER-2/neu (HER2) and mutant epidermal growth factor receptor (EGFRvIII) are overexpressed growth factor receptors present in 30 and 75% of ovarian cancers respectively. Both these proteins elicit immune responses in patients whose tumors express the proteins. Furthermore, preliminary studies in animal and/or human models suggest that antibodies directed against HER2 and EGFRvIII may mediate an anti-tumor response. Some patients with HER2 and EGFRvIII expressing tumors have evidence of low level endogenous antibody responses directed against the tumor antigen. If these antibody responses could be boosted, via immunization, to potentially therapeutic levels, patients may be protected from the development of ovarian cancer or ovarian cancer relapse. Advances in molecular immunology and the definition of antigen recognition by T cells has allowed the identification of co-stimulatory molecules and soluble factors such as cytokines which influence the immune environment. Nucleic acid vaccines (DNA vaccines) which are engineered to encode both the appropriate co-stimulation and tumor antigen for the generation of growth factor specific antibody responses may allow significant levels of endogenous tumor specific antibodies to be generated.
Project 3
Estimating Risk of Ovarian Cancer
Principal Investigator(s): Garnet Anderson, Ph.D.; Susan Johnson, M.D.
Ovarian cancer afflicts approximately 26,000 women in the US each year. More than 75% of these cases will be diagnosed in late stage and their life expectancy is only 3 to 4 years after treatment. Though treatment strategies have evolved over time, prevention and early detection hold the greatest potential for reducing the morbidity and mortality of this dread disease. To succeed, research in prevention and screening requires that we be able to identify populations that are expected to experience large numbers of cases. The more accurately we can target these cases in advance, the more cost-efficient and productive these efforts. Risk-based eligibility has been used successfully in other randomized trials to target individuals most likely to benefit from the intervention. Risk-based screening also holds the potential to increase the positive predictive value of screening and reduce costs.
We propose to develop and validate a statistical model for estimating ovarian cancer risk in post-menopausal women using demographic, reproductive, medical and family history data from the Women's Health Initiative using standard failure time models for risk assessment. We will extend this risk model to examine the potential for serum levels of CA-125 and other promising tumor markers to improve on our estimates of risk. These tumor markers will be evaluated in blood specimens collected from cases prior to their diagnosis and in bloods collected from a sample of similar healthy women using a nested case-control design. The methods of Gail et al for estimating a woman's risk of breast cancer serves as the model for this effort.
In addition, we will learn important information about the relationship between various personal characteristics and marker levels, and the association between marker levels within ovarian cancer and between levels of markers and disease characteristics. These analyses will improve our estimates of risk and assist our understanding of the role that tumor markers play in tracking the development of disease.
Project 4
Methods to Select and Use Biomarker Panels for Screening
Principal Investigator(s): Martin McIntosh, Ph.D.; Beth Y. Karlan, M.D.
The 25% of ovarian cancer cases diagnosed with their cancer confined to the ovary have a five-year survival rate over 90%, but the majority of cases , diagnosed at late stage, have a five-year survival rate of only 20%. Thus, early detection of ovarian cancer may substantially reduce ovarian cancer mortality. Combining imaging technology (such as transvaginal sonography and color Doppler imaging) and biomarker technology (such as CA 125) in screening has great potential to achieve high rates of early detection, but routine screening requires higher sensitivity than has currently been achieved. One approach to improving sensitivity is to discover and use new markers that can complement CA 125 (HER-2/neu, LPA, etc.), and many investigators have shown a substantial gain in sensitivity when using a panel of markers in diagnostic tests for distinguishing benign and malignant ovarian tumors. Another approach improves sensitivity by screening with only CA 125 using a sophisticated algorithm that captures information from longitudinal measurements (the ROM algorithm). Our goal is to combine these two approaches and develop novel algorithms for screening using a panel of longitudinal ly measured biomarkers. Substantial methodologic issues arise when confronting this problem. One issue is selecting which of the dozens of new and existing markers should be used in a panel. Unlike diagnostic testing, adding markers to a panel used for screening can actually decrease sensitivity, and so we must have statistical methods that can select which markers are mutually complementary and best improve sensitivity when used together. How a marker performs depends on how it is used, so that ranking markers requires we that specify algorithms for their use. Our approach decomposes markers' behavior into within and between subject components of variability then generates screening rules using the logic of hypothesis testing. We intend to rank markers by estimating their ability to improve the ROC curves that characterize their performance. The ultimate goal of this project recommends a panel of biomarkers and an algorithm that may be tested in a clinical trial for screening.
Project 5
Improving quality of life for women with ovarian cancer
Principal Investigator(s): M. Robyn Andersen, Ph.D., M.P.H.; Pamela Paley, M.D.
Co-Investigator(s): Nicole Urban, Sc.D.
Patients treated for advanced ovarian cancer frequently report emotional difficulties and reduced QOL due to their cancer experience. Research on psychosocial interventions designed to improve QOL for cancer patients have found that such interventions can reduce anxiety and depression in patients with a variety of cancers, and that these interventions improve survivors' ability to cope with their illness and their QOL. A small but growing body of evidence suggests that psychosocial interventions may also reduce patient's complaints of medical symptoms and improve their health, prolonging survival. Improved health status may be one of the mechanisms by which psychosocial interventions improve QOL. However, the mechanisms by which psychosocial interventions improve survivor health have not been investigated. This study builds on previous work of the investigators using group counseling to improve QOL, and in measurement of QOL. Investigators will develop and test a structured psychosocial group intervention to improve quality of life for women with advanced stage ovarian cancer. The intervention is based on similar programs used in prior studies of cancer patients, and is designed to improve women's quality of life by reducing their levels of anxiety, depression, stress, and feelings of social isolation. The intervention will do this through the provision of a socially supportive group environment and of training in techniques useful for stress management, improved coping with illness, and for improving the quality of social support patients receive outside of the group situation.
Leadership Core
Principal Investigator(s): Nicole Urban, Sc.D.; Mary L. Disis, M.D.; Steven Collins, M.D.
Leadership for the SPORE is based on an innovative interdisciplinary model. To address the needs of the projects, experts in ovarian cancer, translational research and genomics have been identified and recruited to serve as mentors for SPORE investigators who are expert in their own fields but less acquainted with other disciplines that are critical to progress in ovarian cancer translational research. Senior leaders with relevant expertise will interact with each other on a variety of substantive committees to guide the scientific progress of the SPORE. The goal of the Leadership Core is to act as the foundation for scientific interaction, direction, mentoring, and program development.
The senior investigators who comprise the Leadership Core share responsibility for the overall success of the SPORE, including development and use of a substantial ovarian cancer patient population, a specimen repository, and development of tools to reduce ovarian cancer incidence and mortality. The research proposed in the SPORE is translational. Its success is therefore measured by the degree to which it produces useful interventions that have an impact on outcomes. The nature of the research requires that decisions be made all along the way about how the research should proceed. For example, which genes and gene products should be selected for development as markers of ovarian cancer or chemoresistance? Which gene products should be selected for possible development as vaccines? If vectors for the vaccines are not working, what can be done to solve the problem? A Translational Committee will address these questions in a collaborative spirit to facilitate the progress of the research projects.
The Leadership Core also provides a consultation service. To assist the investigators in meeting their translational research objectives, experts in chemoresistance, translational research, behavior change, and early detection of ovarian cancer are available. Statisticians and mathematicians are also available to work with project investigators throughout the project period. They provide scientific review of protocols, power analyses, consulting regarding appropriate statistical analyses and cost-effectiveness analyses, and methods for identifying patterns of genes.
Developmental Research Program (DRP)
As stated in the SPORE Program overview, interventions are needed to reduce ovarian cancer incidence, mortality and morbidity and to improve survival and quality of life (QOL) in ovarian cancer patients. Our goal in the proposed SPORE is to find effective, efficient ways to do this.
It is clear that ovarian cancer mortality and morbidity could be reduced by 1) improving the effectiveness of treatment for the disease, 2) improving detection strategies to detect disease early enough to be cured or even prevented, or 3) developing ways of preventing the disease. Substantial progress in any of these areas would represent a significant contribution to public health efforts to reduce the burden of ovarian cancer, but some goals can be achieved more quickly than others. Efforts of all three kinds are needed to assist women soon (by improving treatment), over time (by improving early detection) and eventually (through prevention). These goals may be met though translation of new findings in behavioral science and molecular biology to effective interventions for ovarian cancer. Our goal is to improve outcomes by facilitating this kind of translation of scientific research to clinical practice to improve outcomes for women. An area of special promise is the potential role of new discoveries in genetics for translation into clinical practice.
As described in the Leadership Core, experts in ovarian cancer, translational research and genomics will be available to interact with each other on a variety of substantive committees - one of which will be to evaluate pilot studies and guide decision making on the use of stored specimens. In recognition of rapidly changing technology and new and novel applications of such technology for research, $100,000-$175,000 will be available per year in the Developmental Research Program budget. The Developmental Research Program is a system for evaluation of pilot research studies and several possible projects that are consistent with the program objectives of the SPORE.
Career Development Program (CDP)
Career development is a critical component of the SPORE and one of the unique features of POCRC. Ovarian cancer is a complex problem that requires the expertise of multiple disciplines to come together to make scientific headway. It is often difficult to lure senior investigators into new fields and model systems different from those on which they built their careers. Our solution to this problem is to engage promising junior investigators, at that start of their careers, to choose experimental models for their particular discipline which focus on ovarian cancer. The benefits of the Career Development Program (CDP) extend to all of the investigators participating in the SPORE, not only to the few new investigators who will be selected for a Career Development Award (CDA) each year. Thus the CDA is a part of a bigger CDP picture which we describe below and in the Leadership Core.
POCRC is a new model program. All junior faculty involved in the SPORE as investigators or contributors of pilot studies will create their own Interdisciplinary Mentoring Committee. They will choose mentors from among the senior faculty (Associate Professor and above) at the UW, FHCRC, or Consortium institutions, and it is anticipated that most will find appropriate mentors from among the senior scientists included in the Leadership Core. Senior investigators, involved in POCRC, are highly motivated to spend time working with promising young scientists who bring energy, creativity and enthusiasm for interdisciplinary collaborations to their work, especially if it results in access to specimens, data and needed expertise. In the SPORE, senior leaders from several institutions will interact with each other on a variety of substantive committees to guide the scientific progress of the younger investigators. The SPORE will benefit the established investigators by giving them an opportunity to become exposed to high quality interdisciplinary work of various kinds. Senior faculty will have the opportunity to provide guidance to all of the projects rather than just to the one they understand best. This model has advantages for the junior investigators as well. They are given a significant opportunity for interdisciplinary career development with a degree of responsibility and independence that they would not have if the senior investigators were dedicated and responsible for individual projects.
This approach builds on two successful FHCRC models. The SPORE CDP is similar to the Mentoring Committee model used in the PHS Division of the FHCRC. All faculty at the level of Assistant Professor in PHS are strongly encouraged to form a mentoring committee and to present their progress to their committee each year as part of the faculty review process. The PHS model has been very successful, but most junior faculty choose mentoring committees that include senior faculty from within their own fields, such as Biostatistics, Epidemiology or Social Science. We will therefore draw as well on a second model. Dr. Hartwell has initiated an Interdisciplinary Training Program for Pre- and Post-Doctoral fellows at the FHCRC. The program is unique in that it provides interdisciplinary training to young investigators to ensure that the next generation of scientists will be proficient in the languages of basic, clinical and public health science and prepared to collaborate with scientists from all of these areas. Senior scientists in the Center are brought together, and learn from one another, in their joint mentoring of young investigators. The Interdisciplinary Training Program at FHCRC is successful because it takes advantage of the opportunity to bring senior investigators together in the interest of training young scientists. The design of the CDP for the SPORE is an extension of this innovative model.
An interdisciplinary group of senior investigators have agreed to work together to mentor junior investigators who are developing careers in ovarian cancer interdisciplinary research. The senior investigators comprise the Leadership Core and share responsibility for the overall success of the SPORE, including meeting the scientific challenges and identifying the translational opportunities. The CDP will provide an unparalleled opportunity for collaboration with a group of scientists who share a vision of ovarian cancer detection, diagnosis, prevention and treatment.
Specimen Core
Principal Investigators: Nancy Kiviat, M.D.; Barbara Goff, M.D.
The Specimen Core has been developed to meet the needs of investigators involved in the projects and pilot studies of the Pacific Ovarian Cancer Research Consortium (POCRC) with respect to tissue acquisition and histologic review, biomarker assay development, and the facilitation of specimen distribution. In addition, a primary goal of the Specimen Core is the development of a large ovarian tissue repository that will ultimately serve as a resource for scientists outside the realm of the POCRC. The advantages of an organized and comprehensive approach to tissue collection and characterization are two-fold. First, a systematic process for specimen collection and review will ensure quality and consistency in pathologic analyses. Second, the centralized management of specimens will facilitate their distribution based upon the priorities defined by a panel of investigators familiar with all POCRC research endeavors.
The research laboratory associated with this core will be responsible for the histologic characterization of all tissue samples collected and stored in the repository. It will also conduct immunohistochemical assays for HER2/neu, Myc, p53, and EGFR as well as screen all tissues for mutations in the p53 gene. This laboratory will also provide consultation and scientific assistance to POCRC laboratories developing potential ovarian cancer screening assays from previously funded work. (Use of Novel Technologies to Identify and Investigate Molecular Markers for Ovarian Cancer Screening and Prevention, 10/98-9/00 DAMD 17-98-1-8649; N. Urban, PI). Following the development and validation of these novel assays, the core laboratory will run these and other assays on several hundred sera in support of Projects 3 and Project 4. It will also be responsible for meeting the specimen collection and processing needs of Projects 1, 2, and 5 and several developmental projects.
Clinical Core
Principal Investigator: Charles W. Drescher, M.D.; Pamela Paley, M.D.
Co-Investigator: Nicole Urban, Sc.D.
Clinical interaction with patients and health care providers is crucial to the success of each research study proposed within the SPORE, and to the long-term success of a translational program of ovarian cancer research. The primary aim of the Clinical Core is to provide clinical expertise, including physician and patient interaction necessary for the successful completion of the research objectives of the SPORE research studies and potential pilot activities. This Clinical Core will provide coordinated and comprehensive procedures for working with physicians to identify eligible women for enrollment in various research studies and activities in the SPORE and interact with the physicians and health care providers in Washington State to translate the research findings back to the community.
The Clinical Core will serve as a liaison with the community for all SPORE research studies, and will be responsible for identification, enrollment and tracking of study participants. The Clinical Core will determine uniform research protocols to be utilized in multiple clinics to approach, consent, and enroll and collect clinical follow-up data for participants donating specimens at time of diagnosis in Projects 1 and 5. The clinical core will also facilitate the collection of biological specimens necessary for Project 2 and Project 4 as well as other SPORE studies.
The Clinical Core will also include a Patient Advocacy Advisory Committee that will work with the investigators to insure that ovarian cancer advocates are represented in all phases of research, paticularly those that involve interaction with patients and women at risk for ovarian cancer.