Leland H. Hartwell - US grants

It has been widely appreciated that biological systems resist environmental, stochastic, and genetic perturbations. This phenomenon has been termed homeostasis, buffering, robustness and canalization. It is becoming possible to investigate these concepts at a molecular level. Recent results indicate that molecular circuits are designed to minimize the phenotypic consequences of perturbation, a process we will term "buffering". We propose to develop paradigms and methods for understanding how genetic variation is buffered using the DNA replication and dNTP synthesis circuits of the yeast, Saccharomyces cerevisiae as test cases. Understanding such buffering mechanisms is important to three broad areas of biology: (1) how genetic variation, the material of evolution, is accumulated in a species; (2) which genes influence the phenotypic expression of genetic variability, for example in the highly variable presentation of human disease in different individuals; and (3) the design principles of biological systems. Our specific aims are the following: 1. Design and employ methods to control the quantity of specific essential proteins in the DNA replication machinery and dNTP biosynthesis pathway. 2. Comprehensively identify the nonessential proteins that influence the capacity of the cell to withstand reduced expression of key essential proteins. 3. Compare the buffering capacity contributed by specific proteins quantitatively and assign them to different epistasis groups. 4. Explore differences among natural isolates of S. cerevisiae in their buffering mechanisms.

The Fred Hutchinson Cancer Research Center (FHCRC) is a comprehensive, multi-disciplinary research center which uses basic and applied research to eliminate cancer as a cause of human suffering. Advances at the FHCRC in the areas of cancer prevention, diagnosis, and treatment are coupled with the progress made toward understanding the mechanisms of neoplastic development as well as basic aspects of cellular and molecular biology common to all organisms. The FHCRC employs over 2,300 faculty and staff and is organized into twenty collaborative programs: Biostatistics, Breast Cancer Research, Cancer Biology, Cancer Prevention Research, Cell Cycle and Growth Control, Clinical Transplant Research, Complications of Cancer Treatment, Developmental Biology, Epidemiology, Gastrointestinal Oncology, the developing program in Genetics, Human Immunogenetics, Immunology, Infectious Diseases, Molecular and Cellular Biology, Molecular Medicine, Molecular Pharmacology, Pediatric Oncology, the developing program in Prostate Cancer Research and Transplantation Biology. The high quality of research conducted in the scientific programs of the FHCRC is reflected in the level of funding from peer-reviewed, research grants and contracts. This application proposes continued support for Cancer Center Support Grant activities including senior leaders, program leaders, staff investigators, planning and evaluation, developmental funding, administration, protocol data review and monitoring, phase I/II trials and 20 shared resources. The aims of the CCSG is to (1) provide support for the research infrastructure of the FHCRC and (2) promote and stimulate interdisciplinary research through enhanced collaborations among the scientific programs.

Scientists at the Fred Hutchinson Cancer Research Center (FHCRC) have established a strong clinical research program in hematopoietic stem cell transplantation and have developed novel approaches for the treatment of malignancies and infectious diseases. Many of these unique strategies incorporate cellular therapy, where specific ex-vivo manipulated stem cell or T cell populations are infused into patients as part of the overall treatment. Several trails are now ongoing at FHCRC involving stem cell expansion, gene therapy, T cell activation, and adoptive immunotherapy for the treatment of infectious diseases caused by CMV and HIV, and malignancies including leukemia, lymphoma, and melanoma. For example, in selected studies T cell clones with the desired antigen specifically must be identified, isolated, in some situations genetically altered, grown to large numbers, stored and infused into patients. Currently these procedures are done in individual laboratories leading to duplication of efforts and raising concerns about reproducibility and quality control. We request matching funds for the construction of a cGMP Cellular Therapy shared resource facility that will permit reproducible production of large quantities of human hematopoietic or immunocompetent cells under the stringent quality conditions that are essential for use in human studies. The Center will provide the necessary ancillary services including cryopreservation and flow cytometry to allow these studies to proceed. This will result in better resource utilization and better quality control of manipulated cell populations for our human studies as required by FDA regulations.

As a consortium cancer center, the role of the administrative leaders is critically important to assure that the Consortium partners (Fred Hutchinson Cancer Research Center, University of Washington, Children's Hospital and Regional Medical Center) plan, coordinate and communicate their activities in a manner that supports Consortium goals and strategies. All of the Consortium partners are well established with large grant bases and have their own administrative staff members who conduct their ongoing business functions. Consortium administrative staff have the responsibility to assure that the following joint cancer center activities are managed in a coordinated and collaborative manner: strategic planning; strategic implementation; program development and evaluation; membership recruitment and review; recruitment support; shared resource development and review; shared resource management; space planning; planning and evaluation; pilot funding initiatives; clinical trials reporting; internal communications re: Consortium activities; ongoing data collection and reporting as required by the CCSG grant; cross-institutional funds flow; grant accounting and expenditure monitoring; and Consortium committee support.

During the past grant period, developmental funds supported the recruitment of 20 productive Consortium faculty members in areas of strategic growth, including 12 clinical investigators working on solid-tumor cancer;44 pilot projects resulting in the acquisition of 27 grants and the publication of 34 papers;and the development of three shared resources in Imaging, High Throughput Genetics and Immune Monitoring. In this competing application, developmental funds are also requested for activities in these three areas as summarized below: 1. Faculty recruitment: CCSG funds are requested to support funding for five new recruits per year in areas of high strategic importance to the Consortium. The Consortium typically recruits 10 to 20 new members per year. 2. Pilot projects: CCSG funds are requested to fund nine to 11 pilot research projects of Consortium members each year. 3. Shared resources: Funding is requested for four shared resources of critical need to Consortium investigators - Bioinformatics;High Throughput Screening, Tissue Bank, and Tumor Models.

CCSG salary support is requested for eight Consortium investigators to serve as staff investigators. Each of the individuals described in this section are principal investigators on peer-reviewed research projects or are clinical investigators actively engaged in translational research; all make important Consortium-wide contributions to the scientific research of other investigators in ways that exceed their formal research collaborations and funded research grants. The individuals and their areas of expertise relevant to their staff investigator role are: Dr. Nora Disis - Translational research for solid-tumor cancers, cancer vaccines Dr. Denise Galloway - Infection-associated cancers Dr. Hannah Linden - Inclusion of underserved populations in clinical trials Dr. Maxine Linial - Interdisciplinary training and education Dr. David Mankoff - Molecular imaging of solid tumor malignancies Dr. John Thompson - Phase I clinical trials Dr. Cornelia Ulrich - Molecular epidemiology Dr. Cassian Yee - Cancer immunotherapy

[unreadable] DESCRIPTION (provided by applicant): [unreadable] The Fred Hutchinson Cancer Research Center (FHCRC) brings together more than 200 FHCRC faculty with research interests in basic, clinical, and public health sciences. Goal is the elimination of cancer through more effective prevention, diagnostics, and treatment, deriving from fundamental insights into the biology of the disease. FHCRC, now in a new consortium with the University of Washington, has received continuous Cancer Center Support Grant funding since 1973. In its 2002 National Cancer Institute (NCI) review, FHCRC's research programs received an outstanding evaluation with regard to their depth and breadth. To achieve these accomplishments, the Center has historically made a major commitment to its science infrastructure, especially the Shared Resources serving investigators from all divisions. Currently, there is a need to upgrade a number of these resources, especially Animal Health, Antibody Development, Genomics, Proteomics, and Scientific Imaging, along with resources providing broad based support, such as Biocomputing, Glassware Services and Research Computing Support. Therefore, matching funds are requested for the upgrade and consolidation of these facilities, first and foremost to strengthen solid tumor research, a need identified in the NCI review. Solid tumor programs are already underway. This upgrade will also serve entire faculty, who will be together on the same campus for the first time in 2004 when Public Health Sciences relocates. It will meet growing demands related to both new technologies and the more sophisticated use of animals in basic and biological research, along with serving faculty recruited in the next five years. [unreadable] [unreadable]

The Fred Hutchinson/University of Washington Cancer Consortium is a new entity formed from the Fred Hutchinson Cancer Research Center, a comprehensive cancer center and 30-year CCSG recipient, and its strong collaborators, the University of Washington and Children's Hospital. The consortium brings roger nearly 300 faculty with research interests in basic, clinical-and public health sciences related to cancer, with a total NCI funding of $112 million. The goal of the Consortium is the elimination of cancer through more effective prevention, diagnostics, and treatment, deriving from fundamental insights into the biology of the disease. New opportunities to reduce the suffering and mortality from cancer are to be found in the interdisciplinary collaboration of scientists in basic, clinical and public health sciences exploiting new information and technology. The Consortium faculty are organized into 16 productive research programs with the emphasis in the Public Health (Biostatistics, Epidemiology, Prevention), Clinical (Transplantation Biology, Clinical Transplantation, Human Immunogenetics, Immunology, Infectious Disease), Fundamental sciences (Basic, Human Biology), and programs that impact all three disciplines (Breast, Prostate, Gynecologic, Genetics, Imaging, and Genetic Instability). During the next grant period the Consortium will seek to develop additional strength in three areas: (1) To increase scientific collaboration and interactions afforded by the new consortium arrangement. (2) To build on existing strengths in immunologic and molecular approaches to solid tumor diagnosis, treatment and prevention. Prior experience in the development of successful new therapeutic approaches for leukemia and lymphoma and the new partnership in cancer clinical care which has been formed between the members of the Consortium, the Seattle Cancer Care Alliance will also contribute to achieving this goal. (3) The Consortium will be a leader in the application of molecular approaches to population sciences. New laboratories will be dedicated to this objective in the new Public Health Sciences Building currently under construction.

DESCRIPTION (provided by applicant):The Fred Hutchinson Cancer Research Center (FHCRC) brings together more than 200 FHCRC faculty with research interests in basic, clinical and public health sciences. To remain competitive with peer institutions, the FHCRC must be capable of accommodating the Animal Health Resource (AHR) space needs for new faculty and growth in the existing programs. There are presently 79 investigators on the FHCRC South Lake Union utilizing animals in approximately 200 active and approved IACUC protocols for their programs of study within the existing facilities. The AHR department has experienced an approximate 69% increase in care days over the past 4 fiscal years, with most of the increase principally due to expanding use of genetically modified rodents among existing faculty. Addition of new faculty to the FHCRC and expanding needs of current investigators are expected to contribute to a continuation of this trend. The FHCRC is currently completing an initial transition to individually ventilated and HEPA filtered caging for its rodent colonies, which will allow increased housing density within existing facility space for its animal populations. Currently there is a need to meet the growing demand, with continued installation and expansion of ventilated rack capacity. Funding is requested for the purchase of 17 double faced and 19 single faced ventilated rack systems with associated accessories. The additional racks requested will allow us to maximize animal housing densities within the existing facility, providing benefit to all Center faculty who rely upon mouse models for their cancer related research projects. There are comprehensive and complementary animal facility use procedures in conjunction with the ventilated caging that address personnel and material flow in all areas of use to provide for exclusion of rodent pathogens which could jeopardize animal health and scientific quality.

DESCRIPTION (provided by applicant): The Genomics Shared Resource of the Fred Hutchinson Cancer Research Center (FHCRC) respectfully requests funds to upgrade components of an existing Affymetrix GeneChip System purchased in 1999. The proposed upgrades consist of replacing a Hewlett-Packard GeneArray scanner with a GeneChip 3000 scanner and modifying 2 GeneChip 400 Fluidic Stations to new GeneChip 450 Fluidic Stations. The GeneChip 3000 upgrade includes a new optical configuration, as well as signal processing advancements that have improved both the sensitivity and reproducibility of GeneChip scanned images. In addition, the new scanner is capable of 1.5625 mu m pixilation and provides the necessary avenue for using the latest in high-density GeneChip array-types, which we currently are unable to access with the existing scanner. The automated features included in both the scanner and the fluidic station upgrades will provide better consistency in data with the added advantage of allowing for increased throughput capabilities without added staffing. The current Affymetrix instrument is housed in the FHCRC Genomics Resources DNA Array Laboratory and is operated by a staff with a combined 14 years of experience with this technology. Over the past 5 years, the resource has processed over 4500 GeneChip arrays and this work has contributed to approximately 20 publications. The upgraded Affymetrix GeneChip System would allow the laboratory to continue to provide this service to FHCRC investigators and provide access to unique array designs and assays unavailable elsewhere.

DESCRIPTION (provided by applicant): The Flow Cytometry Facility of the Fred Hutchinson Cancer Research Center (FHCRC) respectfully requests funds to acquire a Becton Dickinson FACSAria cell sorter to replace an eleven-year-old Becton Dickinson FACS Vantage SE cell sorter. The FACSAria will be equipped with 15 parameter detection, Automated Cell Deposition Unit (ACDU), computer, Aerosol Management System, and table. While the FACS Vantage has been a dependable cell sorter, its limitations have impeded its ability to meet the needs of today's more advanced experimentation. The core user group for the FACSAria consists of members from the major scientific divisions within the FHCRC. As will be noted in the research plan, many of the projects from our varied client base will benefit from the added capabilities of this instrument. These projects will see an immediate enhancement in the research currently being performed due to the FACSAria's heightened sensitivity, its 15-parameter detection, higher throughput, and its ability to sort four populations simultaneously. With the fixed alignment and canned cleaning functions inherent in the instruments design, the FACSAria will benefit the overall functionality of the core facility. The Flow Cytometry facility has operated as a shared resource at the FHCRC for 26 years. It has grown to be an integral part of the scientific research supporting 79 laboratories from 13 programs within the cancer center. With the broad base of applications being run on the facility's cell sorters, the FACSAria would benefit most applications within this shared environment. The FACSAria will address both immediate and future needs of our user community, supporting NIH funded research at the FHCRC.

The Proteomics Shared Resource utilizes state-of-the art mass spectrometry instrumentation to support Fred Hutchinson/University of Washington Cancer Consortium (Consortium) investigators. It is the mission of the resource to provide high quality service in a timely manner for proteomic analyses, including molecular weight determinations of proteins and peptides, protein identification and quantification, and protein modification characterization. This application requests continued support for a resource which continues to fulfill an essential role for research within the Consortium.

antibody

therapy

The Collaborative Data Services (CDS) shared resource provides a broad range of specialized services to support the collection, storage and analysis of complex datasets for Fred Hutchinson/University of Washington Cancer Consortium (Consortium) investigators. CDS provides data acquisition, data management, and database or software development services to over eighty projects each year. The resource has expanded its services, due in part to the increasingly interdisciplinary focus of the Consortium and the general need for data management and tracking. This application requests continued support for a resource which continues to fulfill an essential role for research within the Consortium.

The Animal Health Resource provides a broad variety of animal housing, veterinary and research support services for Fred Hutchinson/University of Washington Cancer Consortium (Consortium) scientists and staff. The facility is fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) and complies with all United States Department of Agriculture (USDA), Public Health Service (PHS), Washington State and local area animal welfare regulations. Comprehensive animal husbandry services are provided for all vertebrate animals used in the Consortium's programs of research. This application requested continued support for a resource which fulfills an essential role for research within the Consortium.

The Research Pathology Shared Resource provides broad based support for research activities within the Fred Hutchinson/University of Washington Cancer Consortium (Consortium). The resource is comprised of two service based laboratories. The Experimental Histopathology lab provides special stains and immunohistology in addition to routine histology services. The Specialized Pathology Section provides support for laser capture microdissection, tissue microarray and expert pathology review for solid tumor specimens from large research studies. This application requests continued support for a resource which fulfills an essential role for peer reviewed research within the Consortium.

The Specimen Processing Resource provides dedicated laboratory support with a strong emphasis on quality control for large population based studies and clinical trials conducted within the Fred Hutchinson/University of Washington Cancer Consortium (Consortium). Established in 1993, the resource provides a broad range of services including the development of procedures for specimen processing and analyses;sample processing and DMA extraction. This application requests continued support for a resource which continues to fulfill an essential role for research within the Consortium.

The Protocol-Specific Research Support program is coordinated within the Research Trials Office, and provides funding for dedicated research nurse and data manager support for the coordination and implementation of important early, innovative, proof-of-principle clinical trials initiated by Consortium investigators. The availability of research nurses and data coordinators with specialized expertise in these complex trials will be critical to launching the Consortium's Phase I novel therapeutics program.

The Fred Hutchinson Cancer Research Center (FHCRC) and University of Washington (UW) offer a broad range of facilities and qualified trained personnel to support the development and manufacturing of novel biological molecules and innovative cell-based therapies for Phase I/I I clinical testing. These facilities are an integral part of the two institution's world-renowned translational research efforts. In support of these efforts, FHCRC and UW have consolidated their three Good Manufacturing Practice (GMP) facilities into one jointly co-administered and operated Therapeutic Manufacturing Unit. Combining the FHCRC Biologies Production and Cell Processing Facilities (previously supported by this grant) with the UWs Gene and Cell Therapy Core Laboratory has allowed these two institutions to further build on their leadership roles in the application of immunotherapy for the treatment of hematological malignancies, and to extend this innovative work to other clinical settings such as autoimmune disorders, melanoma, breast, ovary, and prostate cancer. These facilities permit the reproducible production of large-scale quantities of biological reagents and therapeutic cells under the strict quality control and safety conditions required by the FDA for human studies. Successful development of such materials will have obvious significance for many patients. Further, progress in pursuit of these aims will have relevance for other clinical situations, teaching us valuable lessons about the molecular basis for disease progression, induction of transplant tolerance, response to infectious diseases, and especially about immunotherapy approaches for the treatment of cancer. This application requests continued support for a resource which fulfills an essential role for research within the Fred Hutchinson/University of Washington Cancer Consortium.

The Program in Epidemiology, led by Dr. Thomas Vaughan, includes 18 faculty members, of which 9 faculty are principal investigators on peer-reviewed research projects. The Program received $8.1 million in sponsored support of its research and training activities in 2007, of which $7.8 million was received from sponsors that meet NCI's criteria for peer-review. Program members are faculty at Fred Hutchinson Cancer Research Center (FHCRC), University of Washington (UW) School of Public Health and Community Medicine (SPHCM), and UW School of Medicine (SOM). The overall scientific goals of the Program in Epidemiology are to identify causes of human cancer and its progression;improve our understanding of the basic mechanisms that lead to cancer and its progression; and develop effective primary and secondary prevention strategies. State-of-the-art molecular epidemiology tools and techniques are typically used by investigators in Epidemiology to conduct a wide range of studies to identify physical, chemical and infectious agents, behavioral and host characteristics, and heritable factors that influence a person's chances of developing cancer, and to assess the impact of these factors on the cancer burden in human populations. A rapidly growing area of interest is to identify factors that influence cancer patients'survival and their quality of life. Methodologic work has focused on the development and evaluation of tools to assess the efficacy of cancer screening in the reduction of mortality from cancer and detection of cancer recurrence. During the past grant period, program members authored more than 400 publications, of which 27% were intra-programmatic and 38% were inter-programmatic. PERFORMANCE SITE(

The Prevention Center Shared Resource serves a broad range of investigator - initiated inquiry into the causes, progression, control, treatment and prevention of disease. The Prevention Center supports clinical research investigations on normal and abnormal physiology. In this capacity, the Prevention Center engages in and encourages interdisciplinary, collaborative research within the Fred Hutchinson/University of Washington Cancer Consortium (Consortium). The Center functions as a full service research facility, provides training and certification for technical staff, and serves as a training facility for investigators, fellows, and students. Very few research centers, especially cancer centers, in the country have the expertise or the capability of conducting controlled nutrition interventions. The resource plays a critical role in support of Consortium cancer prevention studies.

The Animal Biolmaging Core (ABIC) provides state of the art animal imaging equipment, including magnetic resonance imaging (MRI), micro positron emission tomography (PET), ultrasound, optical imaging, SPECT/gamma camera, micro computed tomography (CT), and primate PET to support the wide range of scientific projects within the Fred Hutchinson/University of Washington Cancer Consortium (Consortium). A hallmark of successful interdisciplinary imaging research is the assemblage of investigators from diverse backgrounds around promising imaging technologies, with further development of new scientific tools, and novel applications of older technologies, to achieve effective shared resource and research objectives. ABIC is operating under this vision and will provide an essential role in support of Consortium research.

CCSG support for planning and evaluation activities is requested in this competing renewal for meetings of the Consortium's External Advisory Board, senior leadership retreats, and visits from strategic advisors. During the prior grant period, CCSG funds supported highly valuable activities of this kind, including: 1) Five meetings of the Consortium's External Advisory Board that resulted in recommendations that have been influential in the Consortium's recent strategic planning, with most having been implemented or currently undergoing implementation;2) inter-institutional planning retreats with senior leaders and faculty to plan and assess the Consortium's strategic direction, progress, and emerging and developing research programs such as viral pathogenesis and stem/progenitor cell biology;and 3) visits of strategic advisors to provide insight on such topics as the development and application of imaging in research and biomarker discovery and planning a phase I clinical trials program.

The Nutrition Assessment Shared Resource (NASR) provides state-of-the-art methods for collection and analysis of dietary intake data from participants in observational and intervention studies conducted within the Fred Hutchinson/University of Washington Cancer Consortium (Consortium). This shared resource supports multiple standard approaches to dietary assessment, including 24-hour dietary recalls, multiple-day food records, food frequency questionnaires (FFQ) and modified dietary intake records (MDI). NASR also develops and validates new approaches to dietary assessment and analysis of dietary intake data, as needed to fulfill research project needs. NASR continues to fulfill an essential role for peer reviewed research within the Consortium.

Cancer Center Support Grant; programs

The Immune Monitoring Lab provides investigators with a broad spectrum of services and expertise to carry out a range of assays of human proteins and other biological mediators and perform studies where precise evaluations of the immunologic response are required. Resource services include the production of peptide- MHC Class-l tetramers, unique reagents for accessing antigen-specific T cells; molecular assays for T cell receptor (TCR) related analysis, cellular assays for determining cellular function and analytical services using ELISA and Luminex microbead methodology. This application requests continued support for a resource which fulfills an essential role for research within the Fred Hutchinson/University of Washington Cancer Consortium.

The Genomics Resource provides support and technical expertise to researchers with studies employing genomics-based methodologies. Services provided by the resource include capillary-based DNA sequencing and genotyping, high-throughput sequencing-by-synthesis (HT-SBS) technology, and various applications employing microarray technology platforms. This application requests continued support for a resource which fulfills an essential role for peer reviewed research within the Fred Hutchinson/University of Washington Cancer Consortium.

The Biostatistics Shared Resource provides collaborative statistical support to Fred Hutchinson/University of Washington Cancer Consortium (Consortium) members in any of the Consortium research programs. Such support may include any or all of the following: selection of primary and secondary endpoints, study design, sample size and power calculations, randomization procedures, design of data collection instruments, design of early stopping criteria, interim monitoring, data retrieval and analysis and manuscript preparation and review. The resource emphasizes the importance of establishing ongoing and continuing collaboration with biostatisticians during the entire research effort, rather than one-time consultation without appropriate context. Most of the funding for this collaborative effort comes from research grants and contracts. The CCSG supported effort ensures that a stable biostatistical staff is available to Consortium investigators, and in particular provides a resource to support projects that require only a small level of biostatistical support or support on an occasional basis, and to provide assistance to investigators developing new or continuing proposals.

The Cellular Imaging Facility provides access to and training in high resolution, state of the art imaging technologies. These technologies are essential tools for studying the mechanisms of cancer at the molecular, cellular and organismal level. The resource is comprised of two service based laboratories, Electron Microscopy and Scientific Imaging. The resource provides the key tools to enable Fred Hutchinson/University of Washington Cancer Consortium (Consortium) investigators to continue in their studies of underlying cellular mechanisms related to cancer and fulfills an essential role for research within the Consortium.

The most important functions of the shared resource are to establish and maintain databases that enable access to clinical data for research purposes. The shared resource also supports other informatics efforts that enhance the ability of the Consortium to conduct clinical research in an environment increasingly sensitive to human subjects' protections and regulatory accountability. For 30 years, transplant data collection and distribution at Fred Hutchinson Cancer Research Center (FHCRC) has been a centralized activity, with a comprehensive database now of over 12,000 transplants performed at FHCRC that is used routinely by all Consortium members engaged in clinical transplant research. These data are housed in an Ingres database referred to as Gateway. Data from approximately 400 new transplants are added each year and over 3,000 patients are being followed as survivors of transplant. This provides a large database for characterizing the short- and long-term effects of transplant on survival and quality of life. The shared resource comprises dedicated data collection staff responsible for abstracting and entering data from the entire transplant treatment course and a Transplant Informatics Group (TIG) that develops and maintains the Gateway database. The Solid Tumor Informatics Group (STIG) was established in 2002 to develop and operate the computing infrastructure needed to support the solid tumor clinical research programs. Research databases are currently available for prostate and breast cancer subjects; future databases will include gastroenterology, gynecology, and lung/thoracic subjects. This group is responsible for the design, development, enhancement, implementation, and oversight of the Consortium Oncology Data Integration (CODI) data warehouse that aggregates clinical data for solid tumor research. Data enters the warehouse from automated data feeds and web-based data entry systems based on a system called Caisis. Although Caisis originated from an application specifically designed to support a prostate cancer database, it is adaptable to other disease populations. At present the prostate and breast cancer databases are populated with data from approximately 3,500 and more than 16,000 subjects, respectively.

The Clinical Trials Support Office (CTSO) was established in 2002 to provide support for clinical researchers at the three Fred Hutchinson/University of Washington Cancer Consortium (Consortium) institutions, which are Fred Hutchinson Cancer Research Center (FHCRC), University of Washington (UW), and Children's Hospital and Regional Medical Center (Children's). The overarching goal of the CTSO is to provide the infrastructure to support the conduct of efficient, high-quality, regulatorycompliant clinical trials within the Consortium. Toward this end, the CTSO provides centralized training and education to Cancer Consortium members and research staff on appropriate conduct of clinical trials. The CTSO also provides, on a fee-for-service basis, research study staff to implement and manage all aspects of clinical trials. The CTSO is responsible for the clinical trials monitoring program and for Protocol-Specific Research Support activities.

DESCRIPTION (provided by applicant): Project Summary/Abstract Research Computing Support (RCS), the high-performance computing shared resource of the Fred Hutchinson Cancer Research Center (FHCRC) respectfully requests funds to upgrade the current 243-node, high-performance computing (HPC) cluster created in 2004 and expanded in 2006. The proposed upgrade involves retiring the 60 oldest nodes, then adding 123 new compute nodes and their supporting equipment to achieve a cluster capacity of 306 nodes with 1, 2, and 4-core CPUs. The new system offers a 150% increase in processing power and 300% increase in memory capacity. The expanded capacity will enable deep and efficient analysis of genome-wide association and proteomic studies, decrease the currently unacceptably high failure rates of simulation experiments, and accommodate the recent 80% growth in computing intensive research, much of which is not possible on the current cluster. The core user group for the new HPC cluster consists of at least 15 NIH-funded research groups at the Center numerous areas whose biomedical research aimed at eradicating cancer and other diseases is dependent on computationally intensive technical approaches as diverse as protein folding, modeling HIV infection and epidemics, proteomics, genome-wide association studies, multiparameter flow cytometry, and high-throughput sequencing. Several of our researchers are currently experiencing substantial delays in accomplishing their work using our current system. Others have projects that cannot be done at all on the existing instrument. (See Research Projects section for details). RCS has operated the current HPC cluster for six years and has a staff with a combined 146 years of experience. The proposed new HPC cluster will be installed in available space in an FHCRC datacenter. The expanded cluster will address both immediate and future needs of our user community, supporting NIH-funded research at the FHCRC. PUBLIC HEALTH RELEVANCE: We are requesting an expanded high-performance computing (HPC) cluster to provide capacity for the growing computational needs in a broad range of biomedical research studies at our center. Access to fast, reliable HPC clusters is critically important for the translation of the explosion of data produced by large-scale proteomics, genomics, and epidemiological studies into improved prevention, detection and treatment of cancer and other life-threatening diseases. Major areas of NIH-funded research at our center that will greatly benefit from the increased data-analysis capacity and improved performance of the requested HPC cluster include large-scale genetic epidemiologic studies of breast, prostate and colorectal cancers;modeling of vaccine efficacy and infectious disease transmission;and proteomic-based biomarker discovery.

The objective of this contract is to perform all activities required to run the National Cancer Institute's Cancer Information Service Contact Center. The National Cancer Institute's (NCI's) Cancer Information Service (CIS) is a federally funded program that was established in 1975 as an essential part of NCI's cancer education and information efforts. For over 35 years, NCI's CIS has been providing scientifically based, unbiased information to patients, their families and friends, physicians and other health professionals, and the general public about all aspects of cancer.

DESCRIPTION (provided by applicant): This proposal requests funds to purchase a triple quadrupole mass spectrometer to support than 12 NIH-funded projects led by 9 principal investigators at the Fred Hutchinson Cancer Research Center (FHCRC) as well as Cancer Consortium members from the University of Washington and Children's Hospital. Projects that will benefit from this instrumentation span a variety of areas important for cancer research. Specifically the instrument will be used to understand the role of serine/threonine phosphorylation events in cell-cell communication;determine the importance of tyrosine phosphorylation events in Src kinase-modulated signaling pathways;measure the relationship between protein ubiquitination pathways and protein quality control;validate serum biomarkers in cancers of the breast, pancreas, prostate, ovary, and lung;and measure the serum half life of tumor "painting" reagents. Current mass spectrometry instrumentation at the Center (ion- trap and ion-trap/hybrid instruments) is used primarily for large proteomic profiling (e.g., discovery) studies, but is not well suited for applications that require experimental workflows that target specific molecules. Specifically, these projects require an instrument capable of performing 1) qualitative assays of specific protein modifications using precursor ion scanning and 2) highly-sensitive multiplexed quantitative assays for large numbers (100s to 1000s) of peptides in serum using Single/Multiple Reaction Monitoring (S/MRM). The triple quadrupole mass spectrometer is uniquely suited to meet these requirements. Current NIH-funded research with these requirements will demand over 2416 injections onto this instrument per year, or over 87% utilization. If awarded, the triple quadrupole instrument would be operated by the FHCRC Proteomics Shared Resource, where expertise exists to operate, maintain, and manage the instrument, and policies exist to ensure it is accessible to the entire FHCRC and Consortium community, as well as other NIH-funded investigators in the region. Moreover, the FHCRC supports a Computational Proteomics Shared Resource, managed by Center faculty who have expertise and experience to support the computational infrastructure needed to make use of the data generated by the instrument. The requested instrument will address both immediate and future needs of the user community and support NIH-funded research at the FHCRC. PUBLIC HEALTH RELEVANCE: Protein analysis by mass spectrometry is one of the most powerful and expanding analytical tools in cutting-edge biomedical research, and access to proteomics technology is critical to fully understand the biological basis of human disease and to discover and validate protein biomarkers to better diagnose disease and monitor treatment efficacy. The triple quadrupole mass spectrometer requested in this application will provide NIH funded researchers at the Fred Hutchinson Cancer Research Center critically important proteomics data for 1) the early detection of ovarian, lung, pancreatic, prostate and breast cancer through biomarker validation, 2) the development of sensitive assays to detect cancer imaging agents, and 3) the sensitive detection of protein modifications associated with signal transduction pathways, chromatin biology, protein quality control, and cell-cell communication. Ultimately, data produced from this instrument will lead to a better understanding of cancer at the molecular level and improved detection and outcomes for people afflicted with cancer.

CCSG support for planning and evaluation activities is requested in this competing renewal for meetings of the Consortium's External Advisory Board, senior leadership retreats, and visits from strategic advisors. During the prior grant period, CCSG funds supported highly valuable activities of this kind, including: 1) Five meetings of the Consortium's External Advisory Board that resulted in recommendations that have been influential in the Consortium's recent strategic planning, with most having been implemented or currently undergoing implementation; 2) inter-institutional planning retreats with senior leaders and faculty to plan and assess the Consortium's strategic direction, progress, and emerging and developing research programs such as viral pathogenesis and stem/progenitor cell biology; and 3) visits of strategic advisors to provide insight on such topics as the development and application of imaging in research and biomarker discovery and planning a phase I clinical trials program.