Nathan A. Berger, MD - US grants

Many types of DNA damage in eukaryotic cells activate the chromosomal enzyme poly(adenosine diphosphate ribose) polymerase. The increase in the enzyme's activity can cause rapid depletion of cellular levels of its substrate NAD+ and abrupt increases in its product poly(ADP-ribose). The polymer is usually covalently linked to chromosomal proteins, however the function of this posttranslational modificaion has not been defined. We have proposed that the function of the poly(ADP-ribose) synthesized in response to DNA damage is to alter chromatin structure in such a way that regions of DNA damage become more readily accessible to the enzymes of DNA repair. The overall objectives of this proposal re to test this hypothesis for the role of poly(ADP-ribose) synthesis in DNA repair and to define the factors that regulate the activity of poly(ADP-ribose) polymerase and its response to DNA damage. Parallel experiments will be conducted in vitro in an SV 40 minichromosome model and in vivo in cells derived from normal human donors and patients with genetic disorders of DNA repair including xeroderma pigmentosu, Fanconi's anemia, Bloom's syndrome and ataxia telangiectasia. The SV 40 minichromosome, reconstituted with specifc proteins and enzymes, will provide a well defined in vitro model to study the effect of specific factors affecting the interaction of poly(ADP-ribose) synthesis with DNA damage and repair. The studies in cells derived from normal donors and from patients with disorders of DNA repair will provide systems to investigate different aspects of the regulation of poly(ADP-ribose) synthesis. These cells will also be used to further define the possibility that defects in the poly(ADP-ribose) synthesis system may be etiologically related to some of the abnormalities that affect patients with these diseases.

The long-term objective of this proposal is to take advantage of the relation between NAD metabolism, poly(ADP-Ribose) synthesis and DNA repair to design combination chemotherapy protocols for the treatment of malignant disorders. We have shown that nicotinamide analogs, selected for their ability to inhibit poly(ADP-Ribose) polymerase, block the DNA repair process, potentiate the tumorocidal effects of chemotherapeutic agents and increase the lifespan of animals bearing L1210 leukemia or MOPC-315 myeloma. The goals of the present proposal are to identify new, more effective inhibitors of poly(ADP-Ribose) polymerase and optimize the dose and scheduling of their administration to obtain synergistic interactions with chemotherapeutic agents whose cytotoxic mechanism of action is mediated by induction of DNA damage. These studies will be continued in L1210 leukemia and MOPC-315 myeloma and will be extended to solid tumors including the B16 melanoma, Lewis lung carcinoma, and EMT-6 mammary tumor. We have shown that the nucleoside analogs, Tiazofurin and Selenazole, interfere with maintenance of cellular NAD levels. We will seek to develop sequential blockade protocols in which a nicotinamide analog is used as a direct inhibitor of poly(ADP-Ribose) polymerase and Tiazofurin or Selenazole is used to limit substrate availability. Combinations of these two agents with the DNA damaging agents will be evaluated biochemically for their ability to enhance DNA damage and biologically for their ability to produce synergistic tumor cell killing and enhanced survival. Our studies of the mechanisms of cell killing, following treatment with high dose DNA damaging agents, show a dose dependent activation of poly(ADP-Ribose) synthesis which leads to depletion of NAD and ATP pools and consequent cell death. This bears directly on the organ toxicity experienced in recent clinical studies of high dose chemotherapy with autologous marrow rescue for treatment of refractory malignancies. We will analyze metabolite fluxes following high dose chemotherapy to determine whether this pathway, leading to depletion of energy metabolites, accounts for the fatal organ toxicity. In subsequent studies we will seek to prevent this dose limiting toxicity by treatments designed to amplify and protect cellular pools of pyridine nucleotides and energy metabolites.

The Case Western Reserve University Cancer Research Center is a multidisciplinary, clinical and laboratory research center, combining the resources and expertise at Case Western Reserve University School of Medicine and its major affiliated hospitals, University Hospitals of Cleveland, Cleveland Metropolitan General Hospital and the Cleveland Veterans Administration Medical Center. The objectives of the Case Western Reserve University Cancer Research Center are: 1. To improve the prevention, diagnosis and therapy of cancer through research; 2. To rapidly develop the clinical applications of research discoveries and to make these applications available to the residents of the northeast Ohio region as quickly as possible; 3. To provide the stimulation and support facilities for the development of coordinated, interdisciplinary cancer research that will most effectively utilize the resources and expertise available at the associated institutions.

Patients with advanced colo-rectal cancer respond to high dose chemotherapy with alkylating agents in sufficient numbers to provide the basis for cautious optimism that this disease can be cured with biochemical modulation of high dose chemotherapy and autologous bone marrow transplantation. We plan to define the biochemical mechanisms present in colon cancer that limit the antitumor effect of the alkylating agents Melphalan and BCNU and determine how these processes can be modulated to improve the therapy of this disease. A bank of human colon cancer cell lines will be used as models of intrinsic and acquired resistance to Melphalan and BCNU. Resistance pathways will be identified and characterized. Strategies will be developed to overcome resistance patterns primarily associated with the DNA repair pathways and Cellular protective mechanisms including glutathione transferase, thiol metabolism, O(6) alkylguanine alkyltransferase, DNA excision and cross link repair, and poly(ADP-ribose) and pyridine nucleotide metabolism. Molecular Biology studies will be performed to determine the contribution of genes for multidrug resistance, glutathione transferase, metalothione and ras activation to the alkylating agent resistant phenotype. Biochemical modulation protocols developed on the basis of these studies will be tested in vitro in tissue culture and in vivo using a xenograft model of human colon cancer in athymic mice. These studies will provide the rational basis to develop, optimize and test strategies to defeat drug resistance mechanisms. Clinical trials employing biochemical modulators with high dose chemotherapy and autologous bone marrow transplantation will be developed and tested in patients with colon cancer.

The Case Western Reserve University Cancer Research Center is a multidisciplinary clinical and laboratory research center, combining the resources and expertise at Case Western Reserve University School of Medicine and its major affiliated Hospitals, University Hospitals of Cleveland, MetroHealth Medical Center and the Cleveland Veterans Administration Medical Center. The objectives of the Case Western Reserve University Cancer Research Center are: 1. To improve the prevention, diagnosis and therapy of cancer through rearch; 2. To rapidly develop the clinical applications of research discoveries and to make these applications available to the residents of the northeast Ohio region as quickly as possible; 3. To provide the stimulation and support facilities for the development of coordinated, interdisciplinary cancer research that most effectively utilizes the resources and expertise available at the associated institutions. 4. To provide all the services and benefits of an NIH designated Comprehensive Cancer Center to northeast Ohio and the surrounding region. The goals of the Center are accomplished by activities in 7 active programs, 1 developing program and 8 shared resources. PROGRAMS 1. Molecular Biology of Oncogenesis 2. Molecular Virology and AIDS 3. Hematopoietic and Immune Cell Biology 4. Radiation Biology 5. Environmental Carcinogenesis 6. Tumor Metabolism 7. Clinical Trials 8. Prostate Cancer Biology SHARED RESOURCES 1. Molecular Biology 2. Tissue Culture Support 3. Flow Cytometry 4. Radiation Services 5. Histology 6. Athymic Animal Facility 7. Hematopoietic Stem Cell Facility 8. Biostatistics and Clinical Trial

The overall objective of this proposal is to improve cancer morbidity and mortality in older, low income, minority adults from Cuyahoga County, Ohio by implementation of a series of educational interventions amongst health care professionals, religious leaders and community members to improve the knowledge, attitudes and practices regarding utilization and participation in cancer prevention, screening, early detection and treatment programs. This goal will be accomplished by implementation of the following specific aims: 1. A community derived, peer educator based cancer prevention program, already shown to be successful for improving utilization of screening mammography in older, low income, minority women, will be further developed and extended to improve utilization of screening programs for breast, prostate and colorectal cancer and to foster more widespread use of cancer prevention practices in the target community. 2. Formal education conferences will be developed and implemented to inform minority physicians, health care professionals and influential community members such as religious leaders as to the need for appropriate practices of cancer screening and benefits of early detection programs for older, minority adults. 3. A Cancer-Outreach Education Nurse Specialist Program will be developed to provide on-site, office based, education for physicians and other health care professionals to encourage improvement and incorporation of cancer screening and detection procedures at private and community facilities providing health care to older, minority adults. 4. A Minority Community Based Advisory Board will be formally constituted to focus on reduction of cancer morbidity and mortality in the older, low income, minority community and to evaluate and advise on further development and utilization of the programs outlined in the first three specific aims above.

This proposal is to develop a Brain Tumor Research Center at Case Western Reserve University and University Hospitals of Cleveland whose central focus will be the development application of membrane targeted, peptide toxins to improve therapy for malignant brain tumors. The proposal constitutes a synergistic, interdisciplinary, interaction of the clinical, scientific and organizational expertise of physicians and scientists from the Departments of Neurosurgery, Neurology, Neurosciences, Molecular Biology, Medicine, Pediatrics and the Ireland Cancer Center at University Hospitals of Cleveland and Case Western Reserve University. Project 1 will examine the fundamental role of the epidermal growth factor receptor (EGF-R) and the associated signal transduction processes in establishing and maintaining the transformed state in gliomas. Project 2 will examine the role of neurotrophins and the trk family of protooncogenes for their role in growth promotion and establishment of the malignant state in primitive neuroectodermal tumors and astrocytomas. Project 3 will analyze human brain tumors for activation of a specific series of oncogenes including PDGF, Gli and acidic and basic FGF, postulated to be involved in promoting glial cell proliferation. This project will also establish brain tumor derived, human cell lines and test representative samples to evaluate the growth regulating effect of interfering with function and/or expression of these oncogenes. Project 4 will examine the in vitro and in vivo cytotoxic effects of a series of fusion protein constructs, composed of epidermal growth factor (EGF) fused with bacterial exotoxins, on human brain tumors bearing the EGF receptor. Project 5 will develop and test monoclonal antibodies with specificity for malignant astrocyte determinants for their cytotoxic effects on brain tumors. The program will promote the multidisciplinary clinical management of patients with brain tumors and will serve to foster technology transfer from research lab to clinical trials.

The Case Western Reserve University Cancer Research Center is a multidisciplinary clinical and laboratory research center, combining the resources and expertise at Case Western Reserve University School of Medicine and its major affiliated Hospitals, University Hospitals of Cleveland, MetroHealth Medical Center and the Cleveland Veterans Administration Medical Center. The objectives of the Case Western Reserve University Cancer Research Center are: 1. To improve the prevention, diagnosis and therapy of cancer through rearch; 2. To rapidly develop the clinical applications of research discoveries and to make these applications available to the residents of the northeast Ohio region as quickly as possible; 3. To provide the stimulation and support facilities for the development of coordinated, interdisciplinary cancer research that most effectively utilizes the resources and expertise available at the associated institutions. 4. To provide all the services and benefits of an NIH designated Comprehensive Cancer Center to northeast Ohio and the surrounding region. The goals of the Center are accomplished by activities in 7 active programs, 1 developing program and 8 shared resources. PROGRAMS 1. Molecular Biology of Oncogenesis 2. Molecular Virology and AIDS 3. Hematopoietic and Immune Cell Biology 4. Radiation Biology 5. Environmental Carcinogenesis 6. Tumor Metabolism 7. Clinical Trials 8. Prostate Cancer Biology SHARED RESOURCES 1. Molecular Biology 2. Tissue Culture Support 3. Flow Cytometry 4. Radiation Services 5. Histology 6. Athymic Animal Facility 7. Hematopoietic Stem Cell Facility 8. Biostatistics and Clinical Trial

The overall objective of this proposal is to develop new therapeutic regimens for treatment of breast, ovarian, and non-small cell lung carcinomas, based on performance of rationally designed, phase II trials of topoisomerase I inhibitors as single agents, in combination regimens, and in dose-intensive regimens. The program brings together a strong, interactive team of biochemists, pharmacologists, preclinical and clinical investigators to design, implement, and conduct pharmacokinetic and pharmacodynamic guided phase II trials to optimize the use of topoisomerase I directed agents. Microenzymatic assays of topoisomerase I and Il activities and susceptibility to camptothecin analogs will be performed on CT- or bronchoscopic-guided biopsy specimens obtained from tumors of patients participating in these studies. Intensive pharmacology monitoring .will be performed. Pharmacokinetic and pharmacodynamic parameters-will serve as the basis for developing phase II trials involving topoisomerase I inhibitors and other selected agents including cisplatin and/or alkylating agents in non-small cell lung and ovarian cancer; adriamycin and/or alkylating agents in breast cancer. Dose intensification studies of the topoisomerase I inhibitors alone and in combination regimens will be performed using hematopoietic stem cell support. Topoisomerase I inhibitors to be studied in these protocols will include topotecan, CPT-11 and 9-aminocamptothecin. The identification, design, and prioritization of phase II studies will be based on results of biochemical analysis, preclinical models, and/or phase I trials conducted at the CWRU/Ireland Cancer Center and developed in collaboration with staff of the Cancer Therapy Evaluation and Development Program of the National Cancer Institute.

Patients with advanced colo-rectal cancer respond to high dose chemotherapy with alkylating agents in sufficient numbers to provide the basis for cautious optimism that this disease can be cured with biochemical modulation of high dose chemotherapy and autologous bone marrow transplantation. We plan to define the biochemical mechanisms present in colon cancer that limit the antitumor effect of the alkylating agents Melphalan and BCNU and determine how these processes can be modulated to improve the therapy of this disease. A bank of human colon cancer cell lines will be used as models of intrinsic and acquired resistance to Melphalan and BCNU. Resistance pathways will be identified and characterized. Strategies will be developed to overcome resistance patterns primarily associated with the DNA repair pathways and Cellular protective mechanisms including glutathione transferase, thiol metabolism, O(6) alkylguanine alkyltransferase, DNA excision and cross link repair, and poly(ADP-ribose) and pyridine nucleotide metabolism. Molecular Biology studies will be performed to determine the contribution of genes for multidrug resistance, glutathione transferase, metalothione and ras activation to the alkylating agent resistant phenotype. Biochemical modulation protocols developed on the basis of these studies will be tested in vitro in tissue culture and in vivo using a xenograft model of human colon cancer in athymic mice. These studies will provide the rational basis to develop, optimize and test strategies to defeat drug resistance mechanisms. Clinical trials employing biochemical modulators with high dose chemotherapy and autologous bone marrow transplantation will be developed and tested in patients with colon cancer.

building /facility design /renovation; biomedical facility; animal colony;

DESCRIPTION: (Applicant's Description) Case Western Reserve University (CWRU) proposes to develop an interdisciplinary research initiative within the Comprehensive Cancer Center that will integrate aging and cancer research with the goal of being recognized as a formal Aging-Cancer "Program", with a stable base of peer-reviewed funding, including a funded training program, by the time of the CCSG renewal, 08/01/06. "Program" development will be accomplished by leveraging the considerable resources and expertise of cancer researchers and aging researchers associate with the NCI-funded Comprehensive Cancer Center, the NIA-funded Memory and Aging Center, and the VAMC-funded Geriatric Research, Education and Clinical Center (GRECC). This initiative will also leverage Center-associated and non-associated researchers and educators from across CWRU including the Schools of Medicine, Nursing, Arts & Sciences, and Social Services, strategically employing development funds to support faculty recruitment, pilot project expansion, and development of shared resources. The "Program" will develop enhanced Aging-Cancer research studies in the priority areas of treatment, efficacy and tolerance; effects of comorbidity; and the biology of aging and cancer. "Program" development will be mutually guided by the PI, Nathan A. Berger, MD, founding Director of the Cancer Center, who recently completed a 7 year term as Dean of the School of Medicine and Vice President for Medical Affairs, and Co-PI, Jerome Kowal, MD, Associate Dean for Geriatric Medicine and founding Director of the NIA-funded Claude Pepper Older Americans Independence Center and the VAMC GRECC.

DESCRIPTION (provided by applicant): The overall goals of the Case Center for Transdisciplinary Research on Energetics and Cancer are defined organizationally and scientifically. Organizationally, we seek 1) to establish a productive, durable program for transdisciplinary research on energetics and cancer at Case University, 2) to provide pilot project support and training opportunities for new and established scientists who can conduct integrative research on energetics, energy balance and their consequences relative to cancer across the continuum from cancer causation and prevention through survival, and 3) to establish collaborative relations with investigators throughout our university and at other TREC Centers and universities to maximally and synergistically utilize resources to significantly impact problems associated with obesity and cancer. Scientifically, we will conduct a spectrum of mechanism-based laboratory, clinical, and population-based studies to identify targets for prevention and control of obesity and interruption of the linkage between obesity and cancer. The scientific aims are defined by three programs and two pilot projects which are highly interactive and are supported by three TREC core facilities and by the 17 Comprehensive Cancer Center core facilities. Project 1 seeks to determine the intestinal tumor-inducing effect and molecular signaling pathways associated with high-fat diet versus obesity in unique strains of mice with chromosomal substitutions rendering them susceptible or resistant to the obesigenic effects of hig hfat diets. Project 2 will examine candidate gene variance and haplotype, associated biomarkers, and insulin-resistance syndrome related serum markers to understand how insulin-resistance syndrome, related genes and dietary factors work in concert in the etiology of human colon neoplasia. Project 3 will investigate determinants of obesity and metabolic dysfunction during the critical life-transition period of adolescence. This study will capitalize on a unique population cohort followed as part of the Cleveland Children's Sleep and Health Study and will investigate sleep phenotype and sleep disturbances as a novel and important determinant of obesity and its relation to metabolic dysfunction. Pilot Project 1 will investigate the role of ER stress pathways linking the metabolic stress of obesity to development of insulin resistance, its consequences and the identification of molecular targets for interrupting these pathways to prevent health consequences of obesity.

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DESCRIPTION (provided by applicant): The overall goals of the Case Center for Transdisciplinary Research on Energetics and Cancer are defined organizationally and scientifically. Organizationally, we seek 1) to establish a productive, durable program for transdisciplinary research on energetics and cancer at Case University, 2) to provide pilot project support and training opportunities for new and established scientists who can conduct integrative research on energetics, energy balance and their consequences relative to cancer across the continuum from cancer causation and prevention through survival, and 3) to establish collaborative relations with investigators throughout our university and at other TREC Centers and universities to maximally and synergistically utilize resources to significantly impact problems associated with obesity and cancer. Scientifically, we will conduct a spectrum of mechanism-based laboratory, clinical, and population-based studies to identify targets for prevention and control of obesity and interruption of the linkage between obesity and cancer. The scientific aims are defined by three programs and two pilot projects which are highly interactive and are supported by three TREC core facilities and by the 17 Comprehensive Cancer Center core facilities. Project 1 seeks to determine the intestinal tumor-inducing effect and molecular signaling pathways associated with high-fat diet versus obesity in unique strains of mice with chromosomal substitutions rendering them susceptible or resistant to the obesigenic effects of hig hfat diets. Project 2 will examine candidate gene variance and haplotype, associated biomarkers, and insulin-resistance syndrome related serum markers to understand how insulin-resistance syndrome, related genes and dietary factors work in concert in the etiology of human colon neoplasia. Project 3 will investigate determinants of obesity and metabolic dysfunction during the critical life-transition period of adolescence. This study will capitalize on a unique population cohort followed as part of the Cleveland Children's Sleep and Health Study and will investigate sleep phenotype and sleep disturbances as a novel and important determinant of obesity and its relation to metabolic dysfunction. Pilot Project 1 will investigate the role of ER stress pathways linking the metabolic stress of obesity to development of insulin resistance, its consequences and the identification of molecular targets for interrupting these pathways to prevent health consequences of obesity.

DESCRIPTION (provided by applicant): The overall goals of the Case Center for Transdisciplinary Research on Energetics and Cancer are defined organizationally and scientifically. Organizationally, we seek 1) to establish a productive, durable program for transdisciplinary research on energetics and cancer at Case University, 2) to provide pilot project support and training opportunities for new and established scientists who can conduct integrative research on energetics, energy balance and their consequences relative to cancer across the continuum from cancer causation and prevention through survival, and 3) to establish collaborative relations with investigators throughout our university and at other TREC Centers and universities to maximally and synergistically utilize resources to significantly impact problems associated with obesity and cancer. Scientifically, we will conduct a spectrum of mechanism-based laboratory, clinical, and population-based studies to identify targets for prevention and control of obesity and interruption of the linkage between obesity and cancer. The scientific aims are defined by three programs and two pilot projects which are highly interactive and are supported by three TREC core facilities and by the 17 Comprehensive Cancer Center core facilities. Project 1 seeks to determine the intestinal tumor-inducing effect and molecular signaling pathways associated with high-fat diet versus obesity in unique strains of mice with chromosomal substitutions rendering them susceptible or resistant to the obesigenic effects of hig hfat diets. Project 2 will examine candidate gene variance and haplotype, associated biomarkers, and insulin-resistance syndrome related serum markers to understand how insulin-resistance syndrome, related genes and dietary factors work in concert in the etiology of human colon neoplasia. Project 3 will investigate determinants of obesity and metabolic dysfunction during the critical life-transition period of adolescence. This study will capitalize on a unique population cohort followed as part of the Cleveland Children's Sleep and Health Study and will investigate sleep phenotype and sleep disturbances as a novel and important determinant of obesity and its relation to metabolic dysfunction. Pilot Project 1 will investigate the role of ER stress pathways linking the metabolic stress of obesity to development of insulin resistance, its consequences and the identification of molecular targets for interrupting these pathways to prevent health consequences of obesity.

[unreadable] DESCRIPTION (provided by applicant): Obesity has reached global pandemic proportions and is now considered a major crisis in public health. Cancer is among the many comorbid conditions associated with, and probably etiologically related to obesity, with a particularly strong epidemiological relation identified between obesity and colon cancer, post menopausal breast cancer, esophageal adenocarcinoma, uterine cancer, renal cell cancer and others. This proposal seeks funding to support an AACR-TREC-NCI Sponsored Think Tank Conference entitled Energy Balance and Cancer; Mechanisms and Mediators to be held February 24, 25 and 26, 2008 at the Lansdowne Resort Conference Center, Lansdowne, Virginia. [unreadable] [unreadable] While there is strong epidemiologic evidence connecting obesity to cancer, the mechanisms and mediators of this relation as well as their potential interactions are not clearly defined thus limiting attempts to modulate their effects in cancer prevention, progression and therapy. This meeting will examine obesity as a manifestation of disordered energy balance and the resultant mediators and mechanisms connecting these disorders to cancer. High priority themes for discussion include the relation of Obesity, Exercise and Caloric Restriction to Cancer and Mechanisms and Mediators connecting (1) Insulin, Growth Factors and Insulin Resistance to Cancer; (2) Prostaglandins and Eicosanoids to Cancer; (3) Inflammatory and Stress Factors to Cancer; (4) Adipokines and Fat Tissue Products to Cancer and (5) Hormonal Mediators of Adiposity to Cancer. The overall goals of the meeting are (1) to stimulate a provocative think tank deliberation among experts in these and related fields, (2) to better identify potential mediators connecting obesity and cancer, (3) to define their mechanisms of actions and interactions, (4) to outline a research agenda to guide critical investigations of these relations and (5) to identify the most promising candidates to serve as markers and potential targets for both laboratory, clinical and translational research. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Many models of common human diseases and numerous traits of great biological interest vary among inbred strains of laboratory mice. Dissecting their multigenic control and identifying the responsible genes has been notoriously difficult. Chromosome substitution strains, which are a new paradigm for complex trait analysis, enable studies that are difficult or impossible with other genetic resources. CSSs involve a single chromosome substitution on a defined and inbred genetic background. In a CSS panel, each chromosome in the host strain is replaced with the corresponding chromosome from the donor strain. In genetically unique and statistically powerful ways, these CSSs facilitate detection of complex trait genes (QTLs), gene discovery and systems studies. In particular, the completed B6.A/J-Chr CSS panel enabled the first adequately powered study of the genetic architecture of complex traits in mammals. Studies in several laboratories showed that these QTLs in CSSs have unusually large phenotypic effects, that these effects are highly non-additive, and that congenics derived from CSSs provide a quick and reproducible way to reduce intervals to 1-5 candidate genes. CSS panels also have an attribute that is unique among QTL paradigms: a genome survey enables statistically robust phenotypic tests for individual genotypes, rather than average QTL effects across genetically heterogeneous populations. During the previous funding period, we finished several CSSs and made considerable progress towards completion of both the B6.129-Chr and 129.B6-Chr panels. In this application, we propose to bring to 19 the total number of completed CSSs in these two panels; the remaining 25 CSSs can then be completed within two years of the end of the proposed funding period. In addition, these will be the first reciprocal panels of CSSs that should enable unprecedented power to characterize gene interactions in reproducible manner, a task that is extremely challenging with any other paradigm. We also propose a pilot study to test the feasibility of using CSSs to test genetic modifiers for the Mecp2308 mutant mouse model of Rett Syndrome. This study would illustrate a new paradigm to identify and functionally characterize modifier genes and the functional networks in which they act. PUBLIC HEALTH RELEVANCE (provided by applicant): Characterizing the genetic control of mouse models for normal biological processes as well as common human diseases remains an enormous challenge because of multiple epistatic genes and with interactions between genetic and environmental factors. CSSs are a statistically powerful way to dissect the genetic control of these traits, simultaneously enabling gene discovery, functional studies, and systems analysis.

The overall objective of the Case Gl Cancer SPORE Developmental Research Program (SDRP) is to develop innovative and diverse approaches to focus on Gl Cancer translational research across the spectrum from etiology through prevention screening, diagnostics, therapeutics, and survivorship. The SPORE Developmental Research Program will provide 1) financial support, 2) Core Facility Services and 3) intellectual oversight and advice for pilot research projects and investigators. Emphasis will be placed on supporting new investigators as well as established investigators with new approaches to Gl cancers. To stimulate translational research, pilot projects with 2 Co-PI's, one basic and one clinical investigator, will be given preference. For meritorious proposals from individual basic or clinical investigators, the SDRP leadership group will identify complementary translational investigators to serve as advisors. Special plans will be instituted to stimulate Gl cancer research in new areas other than colorectal cancer. The Case Gl SPORE considers the pilot project mechanism to be an important opportunity for initiation of high risk/high impact research and will accordingly provide appropriate prioritization for such proposals. With support from the Case School of Medicine, The Case Comprehensive Cancer Center and SPORE Funds, the SDRP will support up to 4 pilot projects per year at $50,000 each. Availability of pilot projects will be announced by multiple, institution wide, electronic notice systems, by direct communication with department heads and deans and by invitations to specific scientists with exciting new approaches. Pilot proposals will be evaluated using the NIH 9 point scoring system by the SDRP Evaluation Panel composed of selected series of faculty members with involvement in Gl Cancer Research and extensive experience in NIH and other national organization peer review study sections.

The overall objective of the Translational Research Center - F Developmental Research Program (TRCFDRP) is to develop innovative and diverse approaches to focus on Barrett's esophagus and esophageal adenocarcinoma translational research across the spectrum from etiology through prevention screening, diagnostics, and therapeutics. The TRCFDRP will provide 1) financial support, 2) Bioinformatic support 3) TRC-F resources and 4) intellectual oversight and advice for pilot research projects and investigators. Funds for development of pilot research projects are critical to ongoing development and enhancement of the TRC-F and the TRC-F will allocate $150,000 per year for years 2-5 for pilot projects to be used $50,000 per year for pilot projects from within the TRC-F and $100,000 per year for cross center projects. Within-center and Cross Center Pilot Projects will be solicited, reviewed and awarded by the BETRNet Steering Committee on a merit basis with evaluation criteria based on scientific merit, impact, significance, innovation, transdisciplinary characteristics, translational potential, with great significance attached to the potential for the contribution to enhance and extend BETRNet projects as well as the potential for developing into independent research projects. In addition, cross-center pilot projects will consider potential contribution of applications to increase sample size, provide complimentary skills, resources and/or expertise or collaborations with other Translational Research Centers or other multi-institutional cooperative groups. Emphasis will be placed on supporting new investigators as well as established investigators with new approaches. For meritorious proposals from individual basic or clinical investigators, the TRCFDRP leadership group will identify complementary translational investigators to serve as advisors. An innovative approach that we will initiate to engage expertise from both inside and outside the TRC-F will be to post on the Cancer Center website and the national BETRNet website, a series of Research Opportunities in which each TRC-F project will provide a list of research questions, resources, expertise, etc. that will be available for collaborative pilot project research.

The overall objective of the Case Gl SPORE Career Development Program (SCDP) is to develop the next generation of Gl Cancer Translational Scholars who are 1) trained in the broad fundamentals of Gl cancer pathobiology; 2) ready to lead an independent translational Gl cancer research program; 3) oriented and able to most effectively utilize innovative translational and transdisciplinary science approaches to attack and solve problems associated with Gl malignancies; 4) committed to improving all aspects of patient health relevant to Gl malignancies across the spectrum from etiology through prevention, screening, diagnosis, therapy and survivorship, and 5) prepared with sufficient understanding of academic policies and institutional, community and national resources to most effectively support program development and promote academic advancement. The Gl SCDP builds on a strong track record of preparing trainees for successful careers in Gl Cancer Care and Research will support up to 4 SCDP Scholars per year with funds provided from the SPORE Grant, the Case Comprehensive Cancer Center and its NCI sponsored K12 award. Opportunities for translational research training will be provided in collaboration with the CWRU and Clinical Translational Science Award (CTSA) - KL2 Career Development Program. Scholars will be provided with 75% protected time for research and career training. The training program will consist of 4 main core components: 1) Research Project; 2) Research Training; 3) Multidisciplinary Mentoring and 4) Structured Research and Career Development Planning. Each scholar will be provided with a team of 3 mentors including 1) a Research Project Mentor, 2) a Translational Research Mentor, and 3) a Career Development Mentor to guide the scholars to develop successful research and academic careers focused on translational Gl Cancer Research. Scholars progress and performance and that of the overall program will be monitored by the SCDP Scholars Council and scholars will be recruited on both a national and local level with special efforts made to recruit women and members of underrepresented ethnic groups.

Project Summary/Abstract The overall objective of this R25 Youth Enjoy Science (YES) Grant Application from the Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland Ohio, aims to support, develop and implement exciting education, research immersion, outreach and curriculum development activities to attract and mentor URM students in middle and high school progressing to undergraduate college education and teachers to enhance diversity of the cancer healthcare and research workforce. This program is a partnership between the Case CCC, supporting all cancer related research efforts at CWRU, University Hospitals Cleveland and the Cleveland Clinic with the surrounding schools of the Cleveland Metropolitan School District, an economically and academically challenged urban school district, recognized as being one of the poorest major cities in the U.S. This R25 program for URM students, their teachers and families builds and expands on our successful high school student targeted, Scientific Enrichment and Opportunity Program and our recently NCI funded Continuing Umbrella of Research Experience Award. These programs have been developed to engage promising high school students from the CMSD to interact with the SOM faculty to participate in exciting, longitudinal research experience to enhance student interest in pursuing careers in biomedical research and healthcare professions. The R25 YES Program will extend and enhance our efforts to provide a coordinated sequentially integrated approach consisting of 1) Learn to Beat Cancer, a program targeted to engage URM Cleveland area middle school students, their families and teachers to become knowledgeable about cancer research opportunities; 2) YES research opportunities, a program designed to attract promising URM Cleveland high school and undergraduate students to cancer education and research immersion opportunities at the Case CCC; and 3) Teach to Beat Cancer, a program designed to provide special research and education opportunities for teachers of URM students to enhance their cancer related knowledge and education skills, engage in curriculum development and enhance their enthusiasm and ability to promote careers in cancer research and diversity in the biomedical work force.

PROJECT SUMMARY/ABSTRACT The overall objective of the Case GI SPORE Career Development Program (CEP) is to develop the next generation of GI Cancer Translational Scholars who are 1) trained in the broad fundamentals of GI cancer pathobiology; 2) ready to lead an independent translational GI cancer research program; 3) oriented and able to most effectively utilize innovative translational and transdisciplinary science approaches to attack and solve problems associated with GI malignancies; 4) committed to improving all aspects of patient health relevant to GI malignancies across the spectrum from etiology through prevention, screening, diagnosis, therapy and survivorship, and 5) prepared with sufficient understanding of academic policies and institutional, community and national resources to most effectively support program development and promote academic advancement. The GI SPORE CEP builds on a strong track record of preparing trainees for successful careers in GI Cancer Care and Research. It will support 3 and sometimes 4 CEP Scholars per year with funds provided from the SPORE Grant, the Case Comprehensive Cancer Center and CWRU School of Medicine. Opportunities for translational research training will be provided in collaboration with the CWRU and Clinical Translational Science Award (CTSA) ? KL2 Career Development Program. Scholars will be provided with 75% protected time for research and career training. The training program will consist of 4 main core components: 1) Research Project; 2) Research Training; 3) Multidisciplinary Mentoring and 4) Structured Research and Career Development Planning. Each scholar will be provided with a team of 3 mentors including 1) a Research Project Mentor, 2) a Translational Research Mentor, and 3) a Career Development Mentor to guide the scholars to develop successful research and academic careers focused on translational GI Cancer Research. Scholars progress and performance and that of the overall program will be monitored by the CEP Scholars Council and scholars will be recruited on both a local and national level with special efforts made to recruit women and members of underrepresented ethnic groups.

PROJECT SUMMARY AND KEY PERSONNEL Developmental Pilot Projects, Cross BETRNet Pilot Projects, and Other Cross BETRNet Activities Summary: The overall objective of the BETRNet Developmental Research Program (DRP) is to develop innovative and diverse approaches to focus on Barrett's esophagus and esophageal adenocarcinoma translational research across the spectrum from etiology through prevention, screening, diagnostics, and therapeutics. The DRP will provide 1) Financial support, 2) Bioinformatic support 3) Resources and 4) Intellectual oversight and advice for pilot research projects and investigators. Funds for development of pilot research projects are critical to ongoing development and enhancement of the Research Center (RC) and accordingly the RC will allocate $110,000 per year in years 2-5 for pilot projects to be used $40,000 per year for pilot projects from within the RC and $70,000 per year for cross center projects. Within-center and Cross Center Pilot Projects will be solicited, reviewed and awarded by the BETRNet Steering Committee on a merit basis with evaluation criteria based on scientific merit, impact, significance, innovation, transdisciplinary characteristics, translational potential, with great significance attached to the potential for the contribution to enhance and extend BETRNet projects as well as the potential for developing into independent research projects. In addition, cross-center pilot projects will consider potential contribution of applications to increase sample size, provide complimentary skills, resources and/or expertise or collaborations with other BETRNet Research Centers or other multi-institutional cooperative groups. Emphasis will be placed on supporting new investigators as well as established investigators with new approaches. For meritorious proposals from individual basic or clinical investigators, the DRP leadership group will identify complementary translational investigators to serve as advisors. An innovative approach that we will continue to engage expertise from both inside and outside the RC will be to post on the Cancer Center website and the national BETRNet website, a series of Research Opportunities in which each RC project will provide a list of research questions, resources, expertise, etc. that will be available for collaborative pilot project research. Key Personnel: Nathan A. Berger, MD Amitabh Chak, MD, MS Sanford Markowitz, MD, PhD

CASE COMPREHENSIVE CANCER CENTER DISPARITIES SPORE DEVELOPMENTAL RESEARCH PROGRAM (DRP) SUMMARY/ABSTRACT The overall objective of the Case Comprehensive Cancer Center Disparity SPORE Developmental Research Program (DRP) is to develop innovative and diverse approaches to focus on disparities translational research across the spectrum from etiology, prevention, early detection, diagnosis, therapy, survival, disease burden, and mortality in cancers found to disparately affect disadvantaged socioeconomic and racial/ethnic groups. The Case Disparities SPORE DRP will provide 1) Financial support, 2) Core Facility Services, and 3) Intellectual Oversight and Advice for pilot research projects and investigators. Emphasis will be placed on supporting new investigators, as well as, established investigators with new approaches to Disparities Research. To stimulate translational research, pilot projects with 2 Co-PI's, one basic, one clinical and/or one community-based investigator, will be given preference. For meritorious proposals from individual basic, clinical or community- based investigators, the DRP leadership group will identify complementary translational investigators to serve as advisors. The Case Disparities SPORE considers the pilot project mechanism to be an important opportunity for initiation of high risk/high impact research and will accordingly provide appropriate prioritization for such proposals. With support from the collaborating institutions and $50,000 from the SPORE Grant Award, the Case Disparities SPORE will support four pilot projects per year at $50,000 each. Solicitation for pilot projects will be announced by multiple, institution wide, electronic notice systems, by direct communication with Case Comprehensive Cancer Center directors, department heads and deans of participating institutions and by invitations to specific scientists with exciting new approaches. Pilot proposals will be evaluated using the NIH 9 point scoring system by the DRP Evaluation Panel composed of selected series of faculty members representing all participating institutions, with expertise in basic, clinical, translational, epidemiological, sociological and community-based research, and with involvement and experience in NIH and other national organization peer review study sections. Ongoing intellectual and performance oversight, evaluation and advice regarding implementation, conduct and productivity of research will be monitored and guided by a regular series of reports, scientific presentations and meetings between investigators and leadership.

Overall Summary/Abstract The Case Cancer Disparities P20 proposal provides for planning and development of a Specialized Program of Research Excellence (SPORE) in cancer health disparities. This proposal places an emphasis on colon adenoma, precursor lesion of colorectal cancer (CRC), and on breast cancer, which are the two leading causes of cancer death in the United States, and of which, racial disparities persist and are widening. This proposed P20 program builds on the resources of the Case Comprehensive Cancer Center to propose two cutting edge translational Research Projects that use multi-level risk assessment approaches for examining racial difference and epigenetic aging in the development of early colon neoplasia (Project 1) and use systems biology approaches for interrogating molecular mechanisms underlying racial disparities in triple negative breast cancer (TNBC) response to treatment and survival (Project 2). These two Research Projects each are built upon substantial preliminary data, cutting edge technology and methodology, and enabling patient cohorts and tissues to test novel hypotheses with high translational significance. This P20 program will further develop a comprehensive infrastructure for catalyzing a robust Developmental Research Program (DRP) that extend our efforts to other cancers and socioeconomic, demographic and behavioral factors contributing to cancer disparities. A series of 2 core resources support these projects and also establish a strong programmatic infrastructure for transdisciplinary translational research in cancer health disparities. The proposal brings together a highly transdisciplinary team of investigators that work collaboratively through every stages and aims of the proposed research studies to accomplish the translational goal of this P20 application.