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The University of Chicago Breast SPOREOlufunmilayo Olopade, MD, FACP, Principal Investigator Co-Principal Investigator Gini Fleming, MD The UC SPORE aims to develop genetic and imaging-based approaches to the prevention, detection, and treatment of breast cancer in women who are at increased risk of developing an aggressive form of malignancy at a young age. Since this type of breast cancer disproportionately affects young women of African ancestry, a portion of the Breast SPORE tackles the global issue of health disparities among various ethnic and racial groups. The Breast Cancer SPORE is composed of four primary research projects, which are supported by three resource cores. In addition, the Developmental Research Program and the Career Development Program promote novel research endeavors and provide support for young investigators at the University of Chicago
RESEARCH PROJECTSProject 1: Imaging-based determination of breast cancer riskLeader Maryellen Giger, PhD The long-term goal of this project is to further improve multi-modality, image-based markers for assessing breast density and parenchymal structure that may be used alone or together with clinical measures and biomarkers to determine the risk of developing breast cancer. The general hypothesis is that inclusion of automated analyses of the parenchyma will improve the assessment of breast cancer risk. In the future, it is expected that the proposed image-based markers will be useful for improved assessment of patients at high risk for breast cancer and for monitoring the response to preventive treatments. The specific aims are to: Aim 1: Conduct image-based categorization of patient databases using breast density, parenchyma morphology, and automatically extracted parenchyma kinetics. Aim 2: Yield new image-based markers of risk by correlating and modeling various characteristics of breast density and parenchymal patterns with known surrogate markers of risk, such as BRCA1 and BRCA2 genetic mutations and the presence of cancer in the contralateral breast. Aim 3: Develop a better understanding of breast cancer risk by correlating various image markers with developing biomarkers and candidate genes. Aim 4: Use these new models to perform preclinical assessment and translation of the density and parenchymal characteristics of women at high ris
Project 2: Specificity of MRI with optimal temporal, spatial, and spectral sampling for early breast cancer.Leader Gregory Karczmar, PhD This project examines new ways to use magnetic resonance imaging (MRI) to detect pre-cancerous lesions in their earliest stages of development. MRI is excellent in detecting potential malignancies before they become serious; however, this sensitivity leads to many false positives, and physicians often hesitate to carry out certain procedures for fear of performing unnecessary biopsies, surgery, and other treatments. Our team of renowned clinicians are developing and testing MRI techniques that enable us to more accurately determine whether very small lesions are cancerous. Eventually, we hope to destroy the ones identified as cancerous with MRI-directed, minimally invasive procedures, such as ultrasound. In addition, the research project provides an unusual opportunity to correlate MRI parameters with biological markers for malignancy in early breast cancers, possibly leading to improved design of MRI protocols, and interpretation of MRI images. The specific aims of the study are to: Aim 1: Use MRI with improved spectral, spatial, and temporal sampling (MRITSS) to acquire precise images of suspicious incidental lesions found in high-risk women. Determine whether MRITSS increases specificity while maintaining adequate sensitivity. MRITSS will be compared to conventional MRI and pathology will be used as the gold standard. Aim 2: Determine whether conventional and/or MRITSS MRI can distinguish between invasive and intralobular/intraductal cancers. Aim 3: Determine whether breast lesions in African American women who are at risk for high grade, estrogen receptor negative breast cancer are significantly different from those of other women in the study. Aim 4: Test whether there are specific biological markers that are strongly correlated with MRI parameters and explain the appearance of functional and anatomic MRI images of early breast cancers. Biomarkers will include microvessel density, tumor proliferation rate as indicated by Ki67, P53 and HER2 expression.
Project 3: Variation in hormone and xenobiotic metabolizing enzyme genes and breast cancerLeader Olufunmilayo Olopade, MD In this project, we are testing whether sequence variation in genes involved in the metabolism of sex hormones (e.g., estrogen and androgens) and xenobiotics (e.g., environmental toxins and anticancer drugs) increases the risk of breast cancer. To accomplish this, we have extended existing studies to determine whether sequence variation in specific clusters of genes and enzymes influence breast cancer risk. Constructing genetic profiles for use in risk assessment may increase understanding of the role of gene environment interactions in breast cancer etiology and treatment. Moreover, by researching the role of these genes and enzymes in the metabolism of anticancer agents, the information obtained through these studies may help in dissecting the genetic basis of individual variability in response to cancer treatment and, ultimately, lead to individualized therapy. This would lead to reduced breast cancer morbidity and mortality, and improved clinical outcomes for all women with breast cancer. Currently, our specific aims are to: Aim 1: Re-sequence the UGT2B gene cluster based on comparative genomics analyses in ethnically diverse population samples to select specific pieces of DNA for an association study. Aim 2: Examine whether variations in the UGT2B genes are associated with breast cancer risk in women of African descent. Aim 3: Examine whether UGT2B genes and environmental factors are associated with age at diagnosis, tumor grade, and estrogen receptor/progesterone receptor staining.
Project 4: Identifying population specific variants important in toxicity to breast cancer chemotherapyLeader Eileen Dolan, PhD This project is focused on developing and validating a genome-wide, comprehensive approach to test thehypothesis that genetic variation significantly influences susceptibility to toxicities and response associated with breast cancer chemotherapeutic agents. Some cancer therapies that are safe and effective for some people may be toxic to and ineffective for others. Since chemotherapy is one of the mainstays for treatment of breast cancer, this project has great potential for enhancing treatment of the disease. This concerted translational research effort devoted to understanding individual variability in chemosensitivity and toxicity is long overdue within the SPORE program. Although this approach will eventually be applied to a variety of breast cancer agents, we are focusing on fluoropyrimidines (capecitabine) and platinating agents (carboplatin). The project is highly translational, employing two clinical trials and the use of state of the art, complementary approaches including heritability analysis, linkage analysis, expression studies, and association studies. Our specific aims are to: Aim 1: Determine the heritability of variation in the susceptibility to the cytotoxic and apoptotic effects of capecitabine and carboplatin. Aim 2: Perform association studies on CEPH and Yoruban HapMap trios. Aim 3: Examine the relationship between global gene expression patterns and capecitabine and carboplatin-induced cytotoxicity and perform functional studies on candidate genes. Aim 4: Determine whether polymorphisms in candidate genes identified using our global approach are associated with survival or toxicity in breast cancer patients treated with capecitabine.
CORESBiospecimen, Pathology, and Genotyping CoreDirector Husain Sattar, MD The goal of the Biospecimens, Pathology, and Genotyping (BPG) Core is to work with investigators of each SPORE research project and personnel of the Analytic and Informatics Core to ensure efficient and highly coordinated procurement, use, storage and analysis of human biospecimens. The BPG Core maintains a repository of biospecimens including tumor tissue, pre-malignant tissue, adjacent non-malignant tissue, serum, plasma, peripheral blood lymphocytes, and lymphoblastoid cell lines, along with their derivatives such as DNA and RNA samples. The Core’s coding system for all laboratory specimens ensures patient confidentiality and prevents experimental bias. The BPG Core is the integration of the UC Cancer Research Center Human Tissue Research Core Facility and the DNA Sequencing and Genotyping Core Facility.
Analytic and Informatics CoreDirector Nancy Cox, PhD The goal of the Analytic and Informatics Core (AIC) is to work with investigators of each SPORE research project and personnel of the Biospecimen, Pathology, and Genotyping Core to provide an integrated data management system (TraM) and to serve as a resource for the design of experiments and clinical trials, development of innovative statistical methodology, statistical analysis, and publishing translational research generated through the Breast SPORE program. The specific aims of the AIC are to: Aim 1: Complete the development of SPORE databases, including the development of systems to enhance the accuracy and completeness of project data and facilitate the sharing of data and results among SPORE investigators. The systems will link clinical, tissue, and laboratory data in a relational schema and include a web application interface that allow researchers to access databases, perform queries, and export data for statistical analysis. Aim 2: Provide statistical expertise in designing and conducting laboratory experiments, clinical trials, and genetic and epidemiologic studies. Aim 3: Perform statistical analyses and assist in the interpretation of study findings, summarization of results, and preparation of manuscripts for publication. Aim 4: Conduct methodological research to provide research infrastructure for SPORE projects. The AIC will collaborate on the extension of HapMap information to members of CEPH pedigrees not included in the HapMap through use of linkage mapping information on all pedigree members. This research project will substantially improve the power and resolution of Project 4, as well as provide a public resource with phenotype information on CEPH cell lines for use by other investigators. Aim 5: Collaborate and assist all project investigators with the publication of scientific results
Administrative CoreDirector Olufunmilayo Olopade, MD The purpose of the Administrative Core is to facilitate translational research in breast cancer by harnessing intellectual capacity and providing a mechanism for cost-effective utilization of resources. The aims of the Administrative Core are to: Aim 1: Provide necessary administrative assistance to SPORE leaders and investigators. Aim 2: Manage all SPORE finances. Aim 3: Convene all meetings of the SPORE including monthly research meetings and Internal Advisory Board, External Advisory Board, and Executive Committee meetings. Aim 4: Provide day-to-day logistical coordination of the SPORE. Aim 5: Maintain responsibility for administration of the Developmental Research Program and the Career Development Program. Aim 6: Ensure compliance with all institutional, governmental, and NCI-specific regulations and requirements including timely communication and consultation with NCI staff. |
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