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FRED HUTCHINSON CANCER RESEARCH CENTERNicole Urban, Sc.D., Principal Investigator
OverviewThe Pacific Ovarian Cancer Research Consortium (POCRC) is a community-based, multidisciplinary, translational research program that involves clinicians, laboratory scientists and public health scientists from several research and medical institutions along the Pacific Coast. The broad based approach takes full advantage of the scientific expertise available locally and allows the pooling of clinical resources, thus facilitating population-based studies despite the low incidence of ovarian cancer. The themes of the program are 1) risk modeling and early detection of disease, 2) prevention of disease progression using immunotherapeutic strategies, and 3) prognostic classification and development of novel treatments for advanced disease based on identification of genetic alterations that predict disease behavior. Our hypothesis is that through early detection we can improve outcomes significantly, because 1) currently available treatments are more effective in disease confined to the ovary, and 2) we will develop novel, relatively non-toxic treatments that will be particularly effective in early-stage disease. The tools of molecular biology, immunology and immunotherapy are emphasized in the translational research program. The POCRC will conduct four research projects that will be supported by four cores: a Leadership and Administration Core, a Clinical Core, a Specimen Core, and an Informatics Core. Each of the four projects in our Renewal Application relates to at least one of the translational areas outlined in the SPORE guidelines and together the program encompasses all five. Early detection, a key to improved outcomes for women with ovarian cancer and a major focus of our SPORE, is the focus of our first project. Risk modeling, which is needed for implementation of both early detection and prevention programs, is the focus of our second project. Therapy to improve the outcomes for women with advanced disease is the focus of our third project, which explores the potential for eliminating tumor using adoptive T-cell therapy. Identification of molecular targets for therapy and prognostic classification of disease are the goals of our fourth project, which includes functional characterization of potentially relevant genes. All of these projects build on work performed during the current funding period. A Developmental Research Program and a Career Development Program are also included as part of our Renewal.
PROJECT 1: BIOMARKERS FOR OVARIAN CANCER DIAGNOSIS AND SCREENINGPrincipal Investigator(s): Martin McIntosh, Ph.D. Over 90% of women with ovarian cancer confined to the ovary survive five years, but the majority of all cases are diagnosed at a later stage, and few of them survive five years. That strong association between stage and survival suggests that detecting ovarian cancer early could dramatically reduce mortality, and it has been our goal to identify and develop strategies to accomplish this. Presently the only ovarian cancer early detection strategy makes use of a single tumor marker, CA 125, in conjunction with imaging technologies, 1-3 and there is a consensus that improvements are needed, in part because CA 125 is insensitive to early stage disease, and imaging is too non specific on its own. In our current ovarian cancer early detection project we have sought to define a systematic approach to identify many novel markers that could improve disease detection when used with CA 125. We have made substantial progress since our fist efforts to identify novel early detection markers. At present we are completing a cooperative blinded biomarker study to validate these markers of our own discovery along side markers from several research collaborators around the world. It is our goal to identify which of these markers can complement CA 125, and our preliminary results are promising. At the end of this study we will have identified a specific panel of biomarkers that improve CA 125 when used together and has performance suitable for further clinical evaluation. We now propose to further validate these biomarkers in retrospective and prospective screening studies. The success of our research plan relies on our theoretically sound but practical research methods and our valuable serum and data repositories, which allow us the unique opportunity to estimate the sensitivity and pre-clinical period of our markers and marker panel. With this information we intend to select a panel of screening markers that will achieve the earliest detection possible, and we intend to pilot them prospectively in a screening research trial in a population of BRCA mutation carriers. Moreover, because we and others continue to exploit modern biotechnology to identify other putative early detection and diagnostic markers, we will continue to improve our marker panel by developing assays for novel targets and evaluating them, along with our collaborators' markers, in a continuing blinded validation study. At the end of our project we intend to have identified and characterized a panel of high performing novel markers to the point where full clinical evaluation is warranted.
PROJECT 2: RISK MODELINGPrincipal Investigator(s): Garnet Anderson, Ph.D. Ovarian cancer afflicted approximately 23,300 US women in 2002. More than 70% of these cases will be diagnosed in late stage and the 5-year survival for these women is low (25%). Though treatment strategies have provided some improvement in prognosis, 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 identify populations that are expected to experience large numbers of cases. The more accurately we can target these cases in advance, the more cost-effective these efforts are likely to be. We propose to continue our development and validation of a statistical model for estimating ovarian cancer risk in post-menopausal women participating in the Women's Health Initiative. We will determine whether serum levels of CA-125, HE4(WFDC2), and mesothelin(MPF), two candidate markers identified and developed by our research group, can improve our ability to triage women by their estimated risk. These markers will be evaluated in blood specimens collected from WHI Observational Study cases prior to their diagnosis and a sample of the bloods collected from similar healthy women using a nested case-control design. The methods of Gail et al for estimating a woman's risk of breast cancer serve as the model for this effort. The model will be validated in an independent set of cases and controls within the WHI. We propose to use this risk algorithm in the recruitment of women for a Phase I trial of screening in order to determine the feasibility of identifying appropriate at risk women. We will use this rich and unique dataset to examine several biologic hypothesis of interest in understanding the role of these serum markers in ovarian cancer. We will describe marker levels (a) by time prior to diagnosis, to provide estimates of lead time; (b) by disease characteristics, to determine whether these markers are associated with tumor aggressiveness, and (c) by disease risk factors, to provide clues as to whether these markers are related to possible etiologic processes. These analyses will increase our understanding of role of these markers in ovarian disease and with that, how we might better use them as markers of risk, early detection or prognosis, to reduce the impact of ovarian cancer on women's health.
PROJECT 3: ADOPTIVE T CELL THERAPY OF OVARIAN CANCERPrincipal Investigator(s): Cassian Yee, M.D. Recent advances in the identification of tumor antigens recognized by autologous T cells, and improved strategies to augment and monitor the anti-tumor immune response have provided novel immune-based modalities for the treatment of patients with cancer with potentially minimal toxicity and high specificity. The strategy of adoptive T cell therapy involves the isolation and ex vivo expansion of highly selected antigen-specific T cells and represents a precise and rigorous means of controlling the magnitude, specificity and phenotype of an intended immune response. The application of adoptive therapy to the treatment of patients with ovarian cancer, which in its advanced stages following primary therapy is generally incurable, was heralded by the identification of NY-ESO-1 as a potential T cell target antigen. NY-ESO-1 is a cancer-testis antigen that is expressed in 25% of ovarian tumors, limited in expression to adult testis, and is immunogenic, capable of inducing both humoral and cellular responses. . In Specific Aims 1 and 2 of this project, we propose to evaluate the use of adoptively transferred CD4 and CD8 T cells targeting NY-ESO-1 for the treatment of patients with ovarian cancer in clinical studies that evaluate the toxicity, duration of in vivo numeric and functional persistence, and anti-tumor activity of adoptively transferred T cells. Potential obstacles to more effective therapy will be addressed by analysis for the emergence of antigen-loss variants and an evaluation of the process of 'antigen spreading'. The clinical trials proposed in this project will serve as a platform for the translational evaluation of future potential ovarian target antigens that include antigens evaluated in Specific Aim 3. In Aim 3, ovarian antigens previously identified by our group by serologically-directed recombinant expression cloning (SEREX) will be evaluated as potential T cell target antigens. In this way, potential obstacles to a broader and more effective application of T cell therapy can be addressed by expanding both the repertoire of potentially therapeutic target antigens and the pool of eligible patients.
PROJECT 4: MOLECULAR TARGETS FOR PROGNOSIS AND THERAPYPrincipal Investigator(s): Charles Drescher, M.D. Ovarian cancer remains one of the most lethal and clinically challenging of solid tumors. Well over half of newly diagnosed women with ovarian cancer will die of their disease and the relative resistance to standard chemotherapeutic agents displayed by most ovarian cancers represents a significant clinical challenge. Ovarian cancer outcomes would be improved by the identification of molecular markers that can predict or enhance the response of advanced stage serous cancers to cisplatin-based chemotherapy. A way to identify the women least likely to achieve a complete response to standard therapy would be an important first step. Our goal is to develop a prognostic classifier that predicts failure to respond to standard therapy by disease progression or persistence vs. a disease free interval of at least 20 months. The signature will be identified for future refinement and testing in Phase I trials. Evidence is accumulating for alterations in miRNAs in cancer, and it has recently been shown that miRNA expression profiles are more robust classifiers of tumor type than standard mRNA expression profiles. In specific aims 1 and 2 of this project, we plan to correlate the miRNA transcriptome profiles displayed by different ovarian cancers with their clinical/biological behavior and determine the functional significance of specific genes that are differentially expressed in biologically distinct ovarian cancers.
LEADERSHIP AND ADMINISTRATION COREPrincipal Investigator(s): Nicole Urban, Sc.D. The goal of the Leadership and Administrative Core (LAC) is to ensure that translational goals of the POCRC are met. LAC investigators are responsible for ongoing evaluation of scientific and translational progress of all projects. If progress is not sufficient, the Executive Committee comprised of Dr. Urban, Principal Investigator, and co-principal investigators, Drs. Collins, Disis, Drescher, and Karlan, will take necessary action. The executive committee is also responsible for ensuring that cores meet the needs of projects without redundancy or conflict. In addition they are responsible for scientific leadership, including Inter-SPORE communication, coordination and collaborations, and for coordination and integration of POCRC activities, including resource allocation. The LAC will be responsible for coordinating SPORE activities and assuring communication between the cores and the projects. The LAC will provide overall guidance for the translational activities of the SPORE, building on established interdisciplinary collaborations. It will promote, oversee, and evaluate active interaction between the cores and the projects. Through the advisory boards, committees, and working group the LAC will provide the following functions: 1) provide overall management and coordination of the SPORE; 2) meet the scientific advisory needs of the individual research projects; 3) oversee, plan, and evaluate SPORE activities including inter-SPORE activities; 4) promote, oversee, and evaluate interaction of cores and projects; 5) encourage, select, and guide developmental projects; 6) provide mentoring and career development; 7) manage, distribute, and re-allocate SPORE funds and other resources as appropriate; 8) oversee IRB activity. To address the needs of the projects and the cores, experts in ovarian cancer, translational research, early detection/screening, epidemiology, genomics, immunology, statistical methods, informatics, and pathology have been identified and recruited to serve in the LAC. Senior leaders with relevant expertise will interact with each other on substantive committees as well as provide mentorship to POCRC investigators who are experts in their own fields but less acquainted with other disciplines that are critical to career development in ovarian cancer translational research and the overall success of the POCRC.
CLINICAL COREPrincipal Investigator(s): Charles Drescher, M.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 the clinical expertise, including physician and patient interaction, that is necessary for the successful completion of the research objectives of the SPORE studies and potential pilot activities. The POCRC Clinical Core has a proven track record in recruiting, from a broad array of facilities, large cohorts of women at risk for developing ovarian cancer (pre-diagnosis cohort) and women with ovarian cancer at the time of diagnosis (incident cases cohort) and during treatment and follow-up (post diagnosis cohort). Using uniform protocols to approach, consent, enroll and track participants over 1200 women have been enrolled into POCRC SPORE (n=506) inter-SPORE collaborations (n=177) and investigator initiated RO1 funded (n= 592) ovarian cancer research projects. Clinical, pathological and epidemiological data are collected from all participants using standardized data collection instruments. The Clinical Core also includes a Physicians Advisory Committee (PAC) and a Patient Advocacy Group (PAG). The PAC works to ensure that as many participants as possible are included in the research and that the goals and progress of the research are disseminated into the clinical community. The Patient Advocacy Group works directly with researchers at all levels of the SPORE program ensuring that ovarian cancer patients are represented in all phases of the research, particularly those that involve interactions with patients and women at risk for ovarian cancer.
SPECIMEN COREPrincipal Investigator(s): Nancy Kiviat, M.D. Access to well-characterized specimens and laboratory expertise is crucial to the success of each research study proposed within this SPORE program, and to the long-term success of translational research in ovarian cancer. This core will work in concert with all SPORE Cores, Projects and Developmental Research Studies to achieve program goals. The Specimen Core will continue to collect, process, characterize, store, and track tissue, blood samples and other unique specimens, expanding current repository contents for use in SPORE projects and developmental research studies. Our organized and comprehensive approach to specimen accrual and characterization includes (a) a systematic process for specimen collection (b) review to assure quality and consistency in pathologic analyses and (c) centralized management of specimens to facilitate distribution based on priorities defined by a Specimen Review Committee familiar with all POCRC research endeavors. Research laboratories associated with this Core provide critical services to SPORE research projects, including pathology review, antibody development, establishment and characterization of primary ovarian cancer cell cultures and cell lines, and conduct of timely assays for biomarker panel validation. It is essential that the Specimen Core continue to evolve to meet the changing needs of our SPORE program. Towards that end, this Core will emphasize protocols that maximize efficiency and fulfill project needs. For example, processing blood products into 0.3 ml serum and plasma aliquots eliminates harmful freeze-thaw cycles and ensures that the Early Detection Project receives high quality specimens for biomarker evaluation. Furthermore, addition of primary cell cultures to specimen processing protocols facilitates the work of the Immunotherapy and Molecular Targets Projects. Working in conjunction with the other three Cores, the Specimen Core will ensure that all projects, including developmental research studies, have access to a broad spectrum of specimens and data. Lastly, while established to primarily serve the needs of the SPORE projects, the resources of the Specimen Core have been created with sufficient flexibility such that SPORE collaborators may also utilize this very important scientific Core shared resource. Accordingly, specimen inventories will also be available to outside researchers and to other SPOREs through the new Virtual Shared Specimen Repository (VSSR).
INFORMATICS COREPrincipal Investigator(s): Martin McIntosh, Ph.D. The Informatics Core (IC) brings together biostatistical, informatics and database experts to support the information and analysis needs of the individual SPORE projects. We have developed a comprehensive informatics system that currently maintains data for nearly 20,000 specimens from 1,200 women. The IC has also provided analytic support for a variety of studies that have utilized these specimens, resulting in several published and submitted manuscripts dealing with quantitative issues, including the analysis of micro array data. The IC is currently expanding our informatics system to allow web-enabled access to specimen related information through a Virtual Shared Specimen Repository (VSSR) that allows researchers to simultaneously access information about specimens in repositories at FHCRC, Cedars-Sinai and other collaborating institutions. In addition, we have taken a lead role in InterSPORE activities by chairing the InterSPORE Informatics Committee and developing a shared specimen report that describes resources available at the four SPORE sites. During the next phase the IC will continue to manage each project’s information needs and assist in facilitating high quality data analysis. Plans include to continue to provide specimen repository data management (all projects), development of information systems to manage Phase 1 clinical trials (Immunotherapy project), development of a patient tracking system to support an investigational screening trial (Early Detection and Risk Model projects), and continued analysis of microarray and genomics data, including the development of new statistical techniques for the discovery of multigene Component Patterns (CPs) (Early Detection, Molecular Targets & Developmental Research projects). |
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