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FRED HUTCHINSON CANCER RESEARCH CENTER
The 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 Adminstration 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 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 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 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 To improve outcomes for women with advanced serous ovarian cancer it would be very helpful to have a therapeutic intervention that would increase the response to therapy, much as Herceptin does in women with Her2/neu positive breast cancer. Needed would be the novel therapeutic agent itself, and a means of identifying the women most likely to benefit from it. A way to identify the women least likely to achieve a complete response to standard therapy would be a first step in this direction. If successful, a product of the proposed work will be a molecular prognostic classifier validated for potential use in a Phase I trial. It will predict failure to respond to standard therapy by disease progression or persistence vs. a disease free interval of at least 20 months. In addition, as a result of the proposed work, therapeutic targets will have been identified for future development and testing in Phase I trials. Well over half of women newly diagnosed 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. To characterize the molecular abnormalities in ovarian cancer and to determine how these might relate to the differences in biological behavior displayed by these tumors, we have utilized cDNA microarrays to identify specific genes that are differentially expressed in normal vs. malignant ovarian tissue as well as in therapy-responsive vs. therapy-non-responsive ovarian cancers. We propose to extend these studies to validate and refine a molecular prognostic classifier that will identify those women with advanced (stage III/IV) ovarian cancer who are unlikely to respond to standard therapy. We will also functionally characterize genes that are differentially expressed in therapy-responsive vs. therapy-non-responsive ovarian cancer, emphasizing the potential role of these genes in mediating the response of ovarian cancer cells to standard chemotherapeutic agents. Our overall goals are to develop better prognostic markers that will aid in the optimal treatment of women with late stage serous ovarian cancer, and to identify novel therapeutic targets involved in the chemoresistance of ovarian cancer, the primary cause of treatment failure and death in women presenting with advanced disease.
Leadership and Administration Core 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. |
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