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Mayo Clinic Rochester
Overall Abstract The Mayo Clinic Breast Cancer SPORE is being submitted by the Mayo Clinic Cancer Center (MCCC) and Mayo Foundation. This application supports a multidisciplinary team of basic, clinical and population science investigators to perform translational research directed at reducing the burden and mortality from breast cancer. The translational research projects chosen represent extensions of funded research being conducted by SPORE investigators. The science of the SPORE consists of four translational research projects. Project 1 "The Role of CHFR in Tumorigenesis and Paclitaxel-Sensitivity in Breast Cancer" examines Chfr, a polypeptide involved in a novel mitotic checkpoint pathway. This project will elucidate the molecular role of Chfr in the control of mitotic progression, examine its contribution to development of breast cancer and evaluate it as a predictive factor in women with metastatic breast cancer treated with paclitaxel. Project 2 "BRCA2 Missense Mutations and Breast Cancer" addresses the critically important question of which BRCA2 missense mutations predispose to cancer and which are neutral. These studies involve development of risk assessment models using genetic and functional assay data and will be directly translatable to patients with these mutations. Project 3 "Preclinical and Clinical Studies of MUC1 Glycopeptide Vaccine Strategies in Breast Cancer" is directed at developing an optimal breast-cancer based vaccine utilizing glycosylated peptides derived from the MUC1 sequence, which is over expressed and aberrantly glycosylated in over 90% of breast cancers. Project 4 "Aromatase Inhibitors, Breast Density and Plasma Steroid Hormones" evaluates the impact of aromatase inhibitor (AI) therapy on mammographic breast density in women in relation to plasma levels of the AI and steroid hormones and will examine pharmacogenetic associations of haplotype single nucleotide polymorphisms in the cytochrome P450 enzyme system. These research projects will be supported by three cores: Core 1: SPORE Administration, Core 2: Biospecimens and Patient Registry, and Core 3: Biostatistics. A Developmental Research Program has been established to develop promising research initiatives and a Career Development Program will be used to promote the research and career of the most promising junior faculty investigators in breast cancer translational research. The investigators, core facilities, and the developmental research programs in the SPORE are all integrated into the MCCC and, collectively, will advance knowledge and translate findings into the clinic for the benefit of women with breast cancer. Project 1 The microtubule-targeting drugs paclitaxel and docetaxel are widely used in the treatment of breast cancer. Unfortunately, single-agent trials indicate that only 30-50% of patients respond to these taxane-based therapies. The goals of this application are to study a recently described pathway affecting sensitivity to these agents and evaluate the impact of alterations in this pathway in human breast cancer. Intensive studies over the past 20 years have elucidated multiple mechanisms of resistance to taxanes. Recent interest has focused on the role of changes in mitotic checkpoints as determinants of taxane sensitivity. Chfr encodes a 72 kDa polypeptide involved in a novel mitotic checkpoint pathway. Chfr expression is frequently down-regulated in many human cancers. Additionally, Chfr downregulation is associated with enhanced taxane sensitivity. These data raise the possibility that Chfr downregulation not only contributes to tumorigenesis, but also conveys increased sensitivity of breast cancers to taxane-based therapies. We recently generated Chfr-deficient mice and directly demonstrated that Chfr is required for mitotic checkpoint control, maintenance of genomic stability and tumor suppression in mice. Based on these data, we hypothesize that Chfr acts as a tumor suppressor in human breast cancer. Further, we postulate that breast cancers with Chfr downregulation will be more likely to respond to taxane-containing therapy. To test these hypotheses, we propose to: 1) study the mechanism by which Chfr regulates the mitotic checkpoint; 2) examine whether Chfr downregulation contributes to breast cancer development in mice; 3) determine whether Chfr downregulation increases paclitaxel sensitivity in vitro and in mouse models; 4) explore the relationship between Chfr expression and paclitaxel sensitivity in clinical breast cancer specimens. These studies rely on the Breast Biospecimens and Biostatistics Cores. In summary, studies outlined here will elucidate the precise molecular role of CHFR in the control of mitotic progression, evaluate its contribution to breast cancer development and assess its value as a predictive marker of taxane sensitivity in breast cancer patients. Project 2 Interpretation of results from mutation screening of tumor suppressor genes, such as BRCA2, is becoming an increasingly important part of clinical practice. In most cases, this is quite straightforward, but classification of rare missense variants in these genes presents a difficult problem because it is not known whether these subtle changes in the proteins alter function sufficiently to predispose cells to cancer development. As missense mutations account for approximately 35% of all known variants detected by clinical mutation screening in BRCA1 and BRCA2 this has become a significant clinical genetics issue. Here we propose to evaluate and predict whether 200 relatively common BRCA2 missense mutations are disease causing or neutral using a likelihood model that depends on 1) co-segregation of the mutation with disease in affected families, 2) co-occurrence of the mutation with other known deleterious mutations, 3) family history of cancer, 4) evolutionary sequence conservation, and 5) chemical changes in the amino acid due to the mutation. Having classified a number of the 200 missense mutations, the likelihood model data will be considered as the "gold standard" for disease causality and will be used to establish the sensitivity and specificity of a series of BRCA2 functional assays. The validated functional assays will subsequently be applied to the classification of 50 rare missense mutations from the DNA binding domain of BRCA2 that appears to be enriched for missense mutations. Finally, a more formal statistical approach to estimating the probability that a BRCA2 missense mutation is disease causing will be undertaken using a two-component mixture model that utilizes all of the family, functional, and sequence data. The knowledge gained during the study will improve risk assessment and counseling for carriers of the BRCA2 missense mutations and may lead to better evaluation of other missense mutations in this tumor suppressor gene. Furthermore, the data will provide valuable information about how the DNA binding domain of BRCA2 contributes to cancer. Project 3 One of the approaches in the immunotherapy of breast cancer patients involves vaccination with peptides derived from tumor-associated antigens specifically designed to associate with T cells in the context of major histocompatibility complex (MHC) class I and class II molecules. This approach is non-toxic and has the potential of controlling disease and prolonging time to recurrence and ultimately, even serving as a preventive measure. Tumor specific antigens, including MUC1 and tumor associated carbohydrate antigens (TACA) have been shown to elicit tumor-specific cytotoxic T lymphocytes (CTLs) and establish a non-self reactive long-term immune memory. MUC1 is a widely expressed tumor- antigen that is over expressed and aberrantly glycosylated on greater than 90% of breast carcinomas and has been shown to elicit tumor-specific immunity. Several clinical trials using non-glycosylated MUC1 tandem repeat sequences have elicited MUC1-specific CTLs with limited effects on clinical response. However, MUC1 occurs naturally as a heavily glycosylated protein which contains TACA. TACA-containing glycopeptides are appealing CTL-based vaccines as they are widely expressed in breast tumors, their expression is largely tumor specific, and they are induced early during neoplastic transformation. Our objective is to develop optimal breast cancer-based vaccines comparing glycosylated and non-glycosylated natural and anchor-improved peptides derived from the MUC1 sequence. Our hypothesis is that eliciting immunity to glycosylated and/or anchor-improved MUC1 peptides will result in anti-tumor immunity and long-term immune memory. The vaccine design addresses breast cancer prevention as well as immunotherapy after tumor onset. Our specific aims are 1) to generate and characterize CTLs specific for Kb and Db MHC class I-binding MUC1 peptides and assess their effectiveness in the prevention and treatment of spontaneous mammary gland carcinomas in mouse models, 2) to determine in vitro the optimal MUC1 peptides for immunotherapy in HLA-A*0201 individuals, 3) to ascertain "immune competence" of breast cancer patients following primary cancer therapy, and 4) to translate the most effective vaccine strategies in phase I clinical trials in patients with minimal residual disease. Project 4 Understanding variability in the response to breast cancer therapy is important so that the most effective therapy can be administered to patients in a timely manner. Aromatase inhibitors (AIs) have attained a prominent place in the management of postmenopausal women with hormone receptor positive breast cancer, but there are limited data on interindividual variability in responses to this therapy. In Project 4 of the Mayo Breast SPORE we propose to advance our translational research goal of identifying potentially significant responses to AI therapy via changes in plasma steroid hormone levels, changes in mammographic breast density and plasma drug concentrations as well as understanding the genetic influence on these responses to AI therapy. The specific aims of the study are 1) To evaluate changes in percent and area mammographic density in response to AI therapy from pre-treatment to one-year of therapy, 2a) To describe the changes in select plasma steroid hormones (that are either substrates or products of the aromatase activity) from pre-treatment to one year on AI therapy, and correlate with changes in percent and area density over the same time period and, 2b) To describe the variation in plasma anastrozole or exemestane concentrations at one year of AI therapy and correlate with changes in percent and area mammographic density from pre-treatment to one-year. Secondary Aims will examine haplotype tagged SNPs in genes in the cytochrome P450 enzyme system identified through the Mayo Clinic and Indiana University Pharmacogenomics Research Network Projects with changes in percent and area density, changes in hormone levels and drug concentrations. The Primary and Secondary aims will be investigated within an ancillary study to an NCIC CTG clinical trial of aromatase inhibitors, MA27D. Pre-treatment and one-year blood samples, mammograms and questionnaire data will be collected. Aim 2 will also be examined in an ethnically diverse population of 200 women receiving AI therapy (anastrozole) as standard of care at the Mayo Clinic or MD Anderson Cancer Center. Predicting the response to AI therapy via mammographic breast density, steroid hormone levels and genetic variation has the potential for timely identification of women who will not respond to therapy and for whom alternative treatments can be administered.
Core 1 The Administrative Core is responsible for providing administrative and organizational support for the leadership of the Mayo Clinic Breast Cancer SPORE in order to ensure optimal communication between SPORE components, Mayo Clinic Cancer Center, Mayo Clinic as a whole, other breast SPOREs and the National Cancer Institute. This Core is crucial to the optimal integration of all SPORE activities and effective and efficient oversight. The Administrative Core will coordinate the activities of the SPORE Executive Committee, the Mayo Inter-SPORE Advisory Committee, the Internal Scientific Advisory Committee and the External Advisory Committee. All of the committees have specific functions focusing on maximizing the translational research productivity. This Core will also provide administrative support for the activities of the Developmental Research Program and the Career Development Program. The Administrative Core will assist the SPORE Director in coordinating and facilitating the Research Projects and ensuring the proper functioning of the Cores in support of the translational research effort.
Core 2 The goal of this CORE is to provide investigators in this SPORE with high quality patient data, DNA, RNA, serum, and breast tissues from breast cancer patients and normal control patients, and to make these resources available for future translational studies. The activities of the CORE will be conducted in a way that does not compromise patient confidentiality, yet will be as comprehensive as possible in the materials that are provided. The acquisition of human biospecimens and subsequent cellular and molecular analysis of those specimens within the context of patient data are key to many translational studies of cancer. The Mayo Clinic has a strong tradition of biospecimen acquisition and centralized patient data records. Paraffin embedded tissues, histological slides, and associated patient charts from surgeries performed since the first decade of the 1900's are maintained in Mayo's Tissue Registry and the Mayo Archives. Currently, the Biospecimen and Accessioning (BAP) and the Tissue and Cell Molecular Analysis (TACMA) Shared Resources of the Mayo Clinic Cancer Center provide normal and neoplastic human tissues for cancer research at Mayo, and are resources of expertise, collaborative support, and service for pathology, immunohistochemistry, laser capture microdissection, tissue microarray preparation, and nucleic acid extraction. The Biospecimens and Patient Registry Core of this SPORE will be integrated with the existing Shared Resources in order to provide a coordinated, centralized, dedicated program for procuring, processing, and assessing biospecimens and patient data from breast cancer patients and to provide these specimens for research projects within this SPORE and to other investigators with translational research projects. This CORE will interact closely with the Biostatistics Core of this SPORE to integrate data into a single database and to provide specimens that meet the statistical requirements for translational research projects supported by this SPORE.
Core 3 The Biostatistics Core provides statistical expertise and data management support for each of the SPORE projects, the Developmental Research Program projects, and the Cores. Functions of the Biostatistics Core include the development of statistical designs and analysis plans, data acquisition and database development, data form development and processing, monitoring data flow, timeliness, and consistency, monitoring patient safety in studies involving human subjects, data analysis and interpretation, manuscript and presentation preparation, and data archiving. The primary objectives of the Biostatistics Core are:
The existence of the Biostatistics Core assures each investigator access to statistical expertise which includes state of the art data analysis and data management resources as well as provides a mechanism of consistent and compatible data handling. This Core builds upon the innovative and time-tested procedures and systems developed by one of the largest statistical groups in the country, the Mayo Clinic Division of Biostatistics, as well as the NCI-funded Mayo Clinic Cancer Center Statistical Unit.
CAREER DEVELOPMENT PROGRAM The Career Development Program of the Mayo Clinic Breast Cancer SPORE is committed to identifying and mentoring junior faculty with the greatest potential of developing independent programs in translational breast cancer research. This will be accomplished through a rigorous review process aimed at identifying the most talented and promising candidate followed by an intensive, rigorous and effective mentoring program. The mentoring program is based on the development and optimal functioning of a Multidisciplinary Mentoring Committee led by a senior investigator with the scientific expertise and commitment to developing the next generation of translational breast cancer researchers. The Multidisciplinary Mentoring Committee will be composed of the primary mentor and the complementary clinical and/or basic investigator necessary for a comprehensive mentoring program plus a statistician. It is viewed crucial to the success of the awardee that the mentoring be ongoing and robust. This will be accomplished by close oversight by the Director of the Career Development Program of the mentoring process and progress of the awardee. The Director of the Career Development Program in turn will report to the SPORE Executive Committee and the Director of the Mayo Clinic Cancer Center. This intensive oversight process was established because of the firm conviction of the SPORE Director that the development of independent investigators and translational breast cancer research is central to the SPORE mission.
DEVELOPMENTAL RESEARCH PROGRAM The Mayo Clinic Breast Cancer SPORE will make every effort to maximize the number of innovative and high-quality projects in the Developmental Research Program. The goal of this Program is to support innovative, scientifically sound research projects from which findings can be translated into clinically relevant applications that will impact diagnosis and management of breast cancer. This Program will: (1) encourage and solicit innovative translational laboratory, population, and clinical study proposals; (2) encourage and support interdisciplinary collaboration in translational research in breast cancer; and (3) generate new hypotheses that can be tested in larger-scale research projects or clinical trials that can impact breast cancer. The availability of this support provides a stimulus for creativity in the research community, a vehicle for encouraging the interaction of basic scientists and translational investigators, and an opportunity for expanding the research spectrum of the SPORE by pursuing new leads based on discoveries and/or opportunities that arise. The Developmental Research Program will provide $50,000 for one year ($30,000 from SPORE funds and a matching $20,000 from institutional resources) to each of five projects. There will be the possibility of a second year of support based on progress. A process will be established to call for applications on an annual basis and to formally peer review submissions utilizing the expertise of the Internal Scientific Advisory Committee and other experienced investigators. Criteria will be based upon scientific merit, originality, qualifications of the key personnel and interactions, and translational potential. It is anticipated that support of developmental research projects will result in the generation of new hypotheses that can potentially be addressed in existing SPORE-sponsored projects, or through peer reviewed external grant support. It is the intent of the SPORE leadership to encourage and help the investigators to use the data generated by these projects to establish preclinical or clinical trials in breast cancer. In addition the SPORE leadership will work with the investigators to secure independent R01 or Program Project Grant funding before the end of the five years funding period covered by this grant.
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