Olufunmilayo I. Olopade - US grants

DESCRIPTION: The applicant and others have shown recurring deletions of 9p in acute lymphoblastic leukemias, gliomas and lung cancers suggesting that a tumor suppressor gene(s) (TSG) is likely to be located in this region. One proposed candidate gene is CDKN2 (pl6"'IMTS1). This gene is an attractive candidate for a TSG because loss of its normal function as an inhibitor of CDKN4, a cyclin dependent kinase could lead to uncontrolled cell growth. Inactivation of CDN2 by homozygous deletion or point mutation has been reported in a large proportion of cultured cell lines from multiple tumor types. Mutations in CDKN2 occur with less frequency in primary tumors. However, germline point mutations in this gene have recently been described in familial melanoma. Proof that CDKN2 is the 9p tumor suppressor gene that is involved in all tumors with 9p abnormalities awaits demonstration of its ability to suppress tumorigenicity when introduced into cell lines with deletions. However, there is mounting evidence that CDKN2 may not be the only biologically relevant gene in this region. The applicant has cloned the MTAP gene and other transcription units in the critical region on 9p2l. The overall goal of this proposal is to characterize the region of the tumor suppressor locus on 9p and to determine whether there are other TSGs involved. The specific aims are: 1) to identify transcription units in the critical region and to test for alterations of such transcripts in glioma cell lines and in primary tumors. 2) to obtain full length clones of any relevant transcripts from cDNA libraries. Further characterization of the genes will include sequencing, analysis of the predicted function of the protein, and mapping of its genomic structure. 3) to reintroduce identified candidate TSGs from 9p2l-22 into mouse and human cell lines with deletions by minigene or YAC transfection.4) to search for possible clues as to the mechanism of the deletions. 5) to determine the clinical significance of loss of candidate TSGs in gliomas.

The overall purpose of this study is to take DNA samples in parallel with well characterized pedigrees of participants with hereditary cancer. Blood samples will be used to perform genetic testing using markers for specific cancers. This protocol is nearly 100% "core lab only" and this year there are no associated visit or gender and ethnicitiy data reported.

DESCRIPTION (Applicant's Description): The Research Training Grant in Oncology to be utilized by the Section of Hematology/Oncology at the University of Chicago is intended to train the future physician-scientists in Oncology in this country. It is intended to continue a successful training record where over 70% of trainees have obtained first-time full- time academic positions. It is designed to train internal medicine physicians who have completed a full-time clinical year in oncology in the nature of either basic or clinical research in oncology. It is intended that the basic research training will take at least two additional years and possible three. Trainees will be advised and guided by an experienced Program Director and Executive Committee who have participated in their selection of and are committed to their academic development. Trainees will select a sponsor and work within the area of the sponsor. Choices consist of approximately 16 areas ranging from chromosome translocations in hematologic malignancies and drug development through cancer outcomes and research ethics. The trainee will learn how to vertically integrate the knowledge and experience gained so that he or she will be able to be successful as a physician-scientist in the future regardless of whether the major emphasis is in basic or clinical research.

[unreadable] DESCRIPTION (provided by applicant): The overall goal of the present NCI-sponsored Training Program in Medical Oncology at The University of Chicago is to provide outstanding scientific training for postdoctoral fellows in order to prepare them for careers as independent investigators in academic oncology. The direction of the program -- the vertical integration of training in basic and clinical oncology research -- has not changed since the program's inception; however, we have significantly enhanced our training in patient-oriented research in response to a national need. The proposed training in Oncology encompasses several academic units within the Division of Biologic Sciences and includes the Section of hematology/oncology, the Maclean Center for Clinical Medical Ethics in the Department of Medicine, the Department of Health Studies as well as involves a number of research laboratories of clinical and basic research scientists who are members of the University of Chicago Comprehensive Cancer Center. [unreadable] [unreadable] The proposed research training faculty preceptors interact on a number of collaborative research and training efforts. This interaction has been fostered by the close proximity of the investigators at the University of Chicago campus and particularly by their research activities within our comprehensive cancer center. Generally, research programs fall into three distinct areas -- patient-oriented research, translational, and basic science research. Our extensive inpatient and outpatient facilities promote a comprehensive clinical training experience, while our research laboratories allow for the acquisition of basic science skills. Our training program seeks to produce physician-scientists or clinical researchers who possess the skills necessary to bridge the gaps that exist between clinical medicine and basic science. Physicians completing our training program are trained to become the future academic leaders in hematology/oncology who are able to vertically integrate their knowledge from the bedside to the bench or from the bench to the bedside. Trainees will be provided with a problem-oriented approach to research (either a process or an approach within a disease or a specific basic science issue) and will be trained to study research problems using both laboratory and clinical research techniques.

DESCRIPTION (provided by applicant): African Americans and Africans experience a disproportionate burden of pre-menopausal breast cancer for reasons that remain unknown. The identification of persons carrying breast cancer susceptibility genes is a promising approach to understanding the etiology of the disease and developing more effective early detection and prevention strategies. With the cloning of BRCA1 and BRCA2 genes, there is an urgent need to identify mutations among different ethnic populations in order to study mutation spectrum, age-specific penetrance, risks of other cancers, epidemiological risk factors, and effects of modifier genes for mutation carriers. It is more than 6 years since BRCA1was cloned and yet, there is little information available about the role of BRCA1and BRCA2 for ethnic groups other than Caucasians of Northern European ancestry. Our proposal aims to narrow the knowledge gap by examining a large cohort of African American and African breast cancer cases. We propose to ascertain a total of 1000 Nigerian women diagnosed with breast cancer at, or before, age 65, and 1000 controls. All women under the age of 45 and women with a family history of breast or ovarian cancer, or bilateral breast cancer will be screened for BRCA1 and BRCA2 mutations. The incidence and spectrum of mutations identified in these cases will be compared to that previously reported in Caucasian women and to that obtained in 360 African American women from Northern California who are participating in the Cooperative Family Registry for Breast Cancer Studies (CFRBCS). Detailed family cancer history and exposure information will be collected on each participant to determine whether differences exist in exposure history and clustering of breast and other cancers in the families of women with breast cancer, in Nigeria and the United States. Penetrance of BRCA mutations will be estimated for African American and Nigerian kindreds that are segregating a deleterious mutation. UGT1A1 enzyme is one of the major UGT involved in estradiol glucunonidation and also constitutes a major detoxification pathway for toxic or carcinogenic compounds. We have found that populations of African Origin harbor four different alleles of UGT1A1 while non-African populations appear to have only two alleles. In addition, alleles associated with lower gene expression levels reach the highest frequency in populations of sub-Saharan African. Using the resources of the CFRBCS and those collected in this study, the association between single nucleotide polymorphisms and in a number of the genes in the UGTIA cluster and breast cancer will be assessed in a Nigerian case-control study and an African-American case-control study. In addition, UGTIA polymorphisms will be examined as a potential modifies of BRCA1 or BRCA2 cancer risk The accurate definition of genetic risks for young Black women will eventually lead to more accurate clinical risk assessment and the development of targeted prevention, early detection and treatment strategies that should ultimately lead to reduced breast cancer mortality and improved clinical outcomes in young women of African ancestry.

Of all racial/ethnic groups, African Americans and Africans experience a disproportionate burden of premenopausal breast cancer for reasons that remain unknown and understudied. The vast majority of African-Americans originated from West Africa, a region currently estimated to have a population of 200 million persons, of whom more than 120 million is concentrated in Nigeria. In the post genome age, research focused on racial or ethnic group differences is less relevant in view of the dynamic interplay between genes and the environment. Rather, we believe studies should be focused on the individual, each with her unique genetic constitution and history of environmental exposures. We are in a unique position to fill the huge knowledge gaps in the causes of breast cancer in populations of African ancestry by examining a large cohort of African American and Nigerian breast cancer cases. In ongoing work funded through separate R01s, we are collecting comprehensive family and exposure history and have established a large bio-specimen repository of cases and controls from Nigeria that will be invaluable for assessing the reasons why women of African ancestry develop earlier onset and pathologically more aggressive breast cancer. This project aims at testing whether sequence variation in genes involved in the metabolism of sex hormones and xenobiotics (including drugs) influences the risk to breast cancer. We will build on our previous efforts in this area that include large-scale SNP discovery studies guided by comparative genomics analyses involving the UGT1A gene cluster and the CYP3A gene cluster. The goal of this SPORE proposal is to extend our studies and determine whether sequence variation in the UDP-glucuronosyltransferases 2B (UGT2B) family of genes influence the risk to breast cancer. Constructing genetic profiles that could be used to assess risk could also be used to individualize therapy and will increase our understanding of the role of gene environment interactions in breast cancer etiology and treatment. Moreover, because these enzymes are important in the metabolism of anticancer agents, the information obtained through these studies may help in dissecting the genetic bases of inter-individual variability in response to anticancer treatment and, ultimately, lead to individualized therapy. This should ultimately lead to reduced breast cancer morbidity and mortality and improved clinical outcomes for all women with breast cancer. Our specific aims are:1) Perform a re-sequencing survey of the UGT2B gene cluster based on comparative genomics analyses in ethnically diverse population samples to select tag SNPs for association study;2) Examine whether polymorphic variants of UGT2B genes are associated with breast cancer risk in women of African descent and 3) Examine whether UGT2B genes and environmental factors are associated with age at diagnosis, tumor grade, and ER/PR staining.

The Chicago Breast Cancer SPORE program brings together a multidisciplinary team of basic, clinical and population science investigators at the University of Chicago to design innovative research that will reduce the "pain and suffering" from breast cancer using a uniquely global strategy. 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 "Estimation of Breast Cancer Risk from Mammography and Breast MRI" will develop multi-modality, image-based markers for assessing breast density and parenchymal structure that may be used alone or in combination with clinical measures and other biomarkers to quantify breast cancer risk and for monitoring response to chemopreventive agents. Project 2 "Specificity of MRI with optimal temporal, spatial, and spectral sampling in early breast cancer" will examine whether MR imaging with improved spectral, temporal and spatial sampling (MRITSS) leads to improved anatomic and functional imaging in the high-risk population that would benefit most from MRI. Project 3: "Variation in hormone and xenobiotic metabolizing enzyme genes and breast cancer risk" will determine whether sequence variation in genes involved in the metabolism of sex hormones and xenobiotics influence the risk to breast cancer using resources from existing case-control cohorts that are highly enriched for women of African ancestry with ER negative breast cancer. Project 4: "ldentifying population specific variants important in toxicity to breast cancer chemotherapy" to identify genetic variation in target genes that result in an increased risk of toxicities using capecitabine and platinating agents as model drugs. We will identify genetic variants that dictate phenotypes including cytotoxicity and apoptosis by utilizing EBV-transformed lymphoblastoid cell lines from related healthy Caucasians and follow up with studies in African Americans and Yoruban trios from Nigeria. These research projects will be supported by three scientific cores: Core 1: SPORE Administration, Core 2: Biospecimens, Pathology and Genotyping, and Core 3: Analytic and Bioinformatics Core. A Developmental Research Program will advance the rapid translation of the most promising scientific discoveries to the clinic and support the reverse translation of clinical observations in the laboratory. A Career Development Program will be used to support the transition of the most promising junior faculty investigators and to recruit new senior investigators into breast cancer translational research. The investigators, core facilities, the career development and the developmental research programs in the SPORE are all integrated into the University of Chicago Cancer Research Center and, collectively, will translate scientific advances into substantial improvement in breast cancer outcomes.

neoplasm /cancer; university

[unreadable] DESCRIPTION (provided by applicant): The objective of the training program in Basic Medical Oncology at the University of Chicago is to provide an outstanding multidisciplinary research training environment for postdoctoral fellows who have completed internal medicine residency training in order to prepare them for academic careers in oncology. The Section of Hematology/Oncology offers a three-year training in hematology/oncology with the expectation that candidates for research training will complete one clinical year funded by the hospital and then have a minimum of two or three years of training under the proposed training grant depending on whether they perform patient-oriented research or basic/translational laboratory research. The direction of the program - the integration of training in basic and clinical oncology has not changed since the program's inception but we have significantly enhanced our training in patient-oriented research in response to a national need. There are several important structural elements in the research training proposed: 1) access to a diverse population of cancer patients; 2) training under the guidance of a research preceptor(s) within project areas; and 3) specific educational opportunities in the form of course work and special seminars under the various academic units in the University. The research training faculty preceptors interact on a number of collaborative research and training efforts. This interaction has been fostered by the close proximity of the investigators at the University of Chicago campus and particularly by their research activities within our NCI- designated cancer center. Generally, research programs fall into three distinct areas - patient-oriented research, translational/basic science and population science research. In the proposed grant period, we shall continue the successful elements of the program. At the same time, we shall enhance the curricular offerings by providing coursework leading to a Master of Science degree focused on clinical research design, biostatistics, and epidemiologic methods: Our extensive inpatient and outpatient facilities will continue to promote a comprehensive clinical training experience, while our research laboratories will allow for the acquisition of basic science skills, Physicians completing our training program will enter the oncology work force better prepared to become academic leaders in oncology who are able to vertically integrate their knowledge from the bedside to the bench or from the bench to the bedside. With the rapid pace of scientific advances and an aging population prone to develop cancer, well trained oncology work force as proposed in this training program is a wise investment for the nation. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This proposal requests funds to support conference related expenses of approximately 100 physicians, scientists, and other health care professionals (including women and minorities) to attend the 1st annual Special Conference on Familial Breast Cancer in San Antonio on December 12, 2007. The objective of this conference is to stimulate research activities in familial breast cancer by bringing together the best scientists and physicians working in the field while publicizing the resources of the Breast Cancer Family Registry (BCFR), The BCFR is an NCI-funded project since 1995 with the goal of assembling a resource of pedigree, clinical, and epidemiological data and biospecimens on breast cancer families from the US, Canada and Australia. There are currently six participating sites, three of which are using population-based ascertainment and three a clinic- or community-based scheme. To date, over 13,000 families have been enrolled in the BCFR. This special conference will emphasize family based basic science, translational and clinical studies and will serve as a forum for promoting and disseminating the latest scientific advances in the prevention and management of familial breast cancer. In addition, the training needs of young investigators who wish to pursue investigative careers in familial breast cancer will be addressed through lectures, workshops and panel discussions.

The Cancer Risk and Prevention Program (Program 6) is an extremely interdisciplinary program involving 32 members from 11 Departments representing basic, translational, and clinical investigators. Members have a total of $ 7,327,303 in peer-reviewed funding, including $1,403,749 from the NCI. Over the past grant cycle, Program 6 members generated a total of 269 peer-reviewed publications, including 8% intraprogrammatic, and 25% interprogrammatic publications. The overall objectives of the Cancer Risk and Prevention Program are to understand the genetic, psychological, behavioral, and socio-environmental basis of cancer and to disseminate cancer control efforts through research in our local community. The specific scientific goals are (1) to elucidate the genetic and environmental basis, as well as the mechanisms of progression, for common cancers (breast, ovarian, colorectal, prostate, lung, skin, and blood), and to translate this new knowledge into clinical and public health practice;(2) to develop animal models for chemoprevention studies and develop biomarkers for early detection of cancer;(3) to identify genetic, psychological, and bio-behavioral bases of cancer risk and prevention;and (4) to establish an organized outreach research effort in the Southside Chicago neighborhoods to enhance and empower their participation and utilization of University of Chicago research, educational and clinical services, thereby reducing the disparities in cancer and other health outcomes and their modifiable determinants in the community. The heterogeneity of research within the Program is a strength, but it also presents challenges, given the wide-ranging foci of scientific investigations from basic scientific research in carcinogenesis through preclinical and clinical translational research. Particular strengths of the Program include molecular epidemiology, basic and clinical studies in addiction and high-risk health behaviors, and studies of environmental toxicity and population-based genetics. This program encompasses transdisciplinary interactions and collaborations fostered by program-specific activities, by the close proximity of the investigators at the University of Chicago campus and, particularly, by the large collaborative research grants, such as the Center for Interdisciplinary Health Disparities Research, Breast Cancer SPORE, PO1s, and training grants within the Program.

PROJECT SUMMARY/ABSTRACT The overall goal of the dual-track University of Chicago Paul Calabresi Career Development Award for Clinical Oncology is to increase the number of highly skilled clinicians (M.D.s, D.O,s, Pharm.D., nurses with PhD or equivalent) and non-clinician postdoctoral researchers who are capable of designing and testing innovative hypothesis-driven clinical therapeutic research protocols in clinical trial settings (pilot/Phase I, Phase II and Phase III trials). To do this, we have created a tightly structured and mentored education program within an academically rigorous training environment that prepares the most compelling senior fellows or junior faculty in clinical oncology for careers in patient oriented research. The program is anchored within our Comprehensive Cancer Center and led by Olufunmilayo Olopade, MD along with Walter Stadler, MD with strong support from an Executive Committee as well as Internal and External Advisory Committees. The 78 research training faculty preceptors have NIH or equivalent peer- reviewed funding, interact on a number of collaborative research and training efforts and are well qualified to serve as potential mentors for the five trainees per year participating in this K12 program. Each trainee is appointed for a minimum of two years. In this renewal application, we shall continue successful elements of the program in clinical pharmacology, genomics and immunotherapy while enhancing training opportunities in emerging fields of clinical informatics, data science and microbiome research. The Paul Calabresi K12 Scholars Program is our highly mentored, didactic coursework-intensive program, and ?hands on? clinical research training which results in a Master of Science in Clinical Investigation. Leveraging clinical research infrastructure across University of Chicago Medicine, we have also created a flexible set of integrated interdisciplinary courses in translational science that blends entrepreneurships, cancer genomics, immunology, pharmacogenomics and community based clinical trials network. Of the 18 trainees who have completed the program since 2010, 13 (72%) are currently in academic careers, of whom 7 (54%) hold appointments at the Associate Professor level. Moreover, these 18 trainees have published a total of 176 oncology research papers, and are Principal Investigators or Co-Investigators on 56 oncology research grant awards. Of significance, 7 of 14 (50%) appointments to the program in the last funding cycle were women or members of underserved minority groups. An explicit goal of this Paul Calabresi Scholars program, as with all training programs in our institution, is that its training opportunities and benefits will extend far beyond the relatively few scholars whose stipends it will provide. The program has had a transformative and global impact and is reaching into the larger oncology trainee community in Chicago and to trainees in other countries who come to our Institution as Global Oncology Scholars. Thus, the benefit that accrues from the program's implementation and productivity is substantial and will increase the number of highly skilled clinicians and non-clinicians conducting cancer clinical trials.

DESCRIPTION (provided by applicant): The paucity of data on the genetic epidemiology of breast cancer for racial/ethnic groups other than those of European ancestry hinders the development of innovative interventions to reduce health disparities. Women in the African Diaspora experience a disproportionate burden of pre-menopausal breast cancer in comparison to all other races for reasons that remain unknown and understudied. This higher proportion of early-onset breast cancer might suggest a stronger genetic component in these populations. Genome-wide association studies (GWAS) have revealed several genetic loci that confer risk of breast cancer. Because all GWAS started the discovery stage in women of European ancestry and replicated mainly in women of European ancestry, we propose a novel approach for a GWAS in indigenous African women to identify alleles associated with breast cancer risk which will then be replicated in other populations. This innovative design builds on our current understanding of the etiologic heterogeneity in breast cancer and the distribution of breast cancer molecular subtypes which differ between women of African ancestry and women of European ancestry. The major objective of the proposed studies is to get to the "root" causes of breast cancer by identifying breast cancer risk alleles in a pooled sample of women of African ancestry and to replicate our findings in other populations. To achieve this objective, we propose the following specific aims: 1) Genotype 1,796 breast cancer cases and 1,988 controls of African ancestry using the Illumina Human1M BeadChip platform. These include 944 cases and 665 controls form Ibadan, Nigeria, 171 cases and 378 controls from Barbados, and 681 cases and 945 controls from Chicago, Detroit, Philadelphia and Baltimore;2) Conduct both standard and novel genetic analyses of the data to map genes associated with breast cancer susceptibility, 3) Verify genotyping and carry out fine-mapping studies in genes or regions showing association with breast cancer risk and related clinical phenotypes and 4) Replicate in other African American and non-African American populations. By pooling unique resources from studies throughout the African Diaspora, this study has the potential to identify risk alleles in several genes that contribute to increased breast cancer risk and may have implications for early detection, prognosis and treatment of breast cancer in ALL women. This should ultimately lead to improved outcomes for those who suffer a disproportionate burden of early-onset breast cancer. PUBLIC HEALTH RELEVANCE: Of all the racial/ethnic groups in the United States, African Americans have the highest mortality rate of breast cancer diagnosed in women under 35 years of age, and in Africa, breast cancer is a uniformly fatal affliction of young women, in part, due to poor access to care and ignorance of the disease. This project focuses on the understudied global problem of breast cancer in the African Diaspora and attempts to translate recent advances in genomics research to benefit women who are at risk of developing hormone receptor negative breast cancer, an aggressive form of breast cancer that often affects younger women. Better understanding of the genetic risks of breast cancer for women in the African Diaspora should lead to better clinical risk assessment and the development of more effective strategies for prevention, early detection and treatment of breast cancer for ALL women.

DESCRIPTION (provided by applicant): It is now well recognized that African Americans experience a disproportionate burden of pre-menopausal breast cancer and higher mortality rates in comparison to other racial/ethnic groups. Recent studies demonstrate that African Americans are more likely to develop triple-negative breast cancer (TNBC) or basal- like breast cancer in particular. We recently showed that indigenous West Africans, the founder population of African Americans had even higher proportions of TNBC than do African Americans. We have recruited 1233 breast cancer cases and 1101 controls in Phase 1 of the Nigerian Breast Cancer Study (NBCS) and recruitment of additional 1500 cases and ethnicity & age-matched 1500 controls is ongoing. In addition, we are conducting a genome-wide association study (GWAS) of breast cancer in women of African Ancestry to study common variants for breast cancer and results will be available in autumn 2011. Here, we propose a high- throughput whole genome DNA sequencing and computational biology approach to examine rare, moderate- penetrance variants for breast cancers and expand the analysis of ethnic diversity in breast cancer genomes. Our specific aims are to: 1) fully sequence genomes (WGS) of normal blood and matched primary breast tumors from 200 well-phenotyped cases and 200 controls to identify germline and somatic variants for triple negative breast cancer. We will distinguish inherited from somatic variants by comparing variants identified in tumors with the paired normal blood samples and the healthy controls to evaluate the etiologic effect of the inherited variants; 2) Validate selected genes/variants in >5000 breast cancer cases and >5000 controls of African and non-African ancestry. We will first impute rare genotypes identified by whole genome sequencing into all the GWAS samples to conduct an in silico replication. Then, we will perform replication in the African American Breast Cancer Consortium, which includes Black Women's Health Study and the Triple Negative Breast Cancer Consortium. Our access to other Consortia including BCAC, CIMBA and Post GWAS U19 will provide other cohorts for replicating our studies. This integrative approach will increase our power to identify associations between rare inherited variants and the most aggressive form of breast cancer in an understudied but unique population. The replication of our study findings in other populations and our data sharing plans will bring enormous public health benefit by harnessing genomics and biotechnology to improve global health equity and reduce health disparities.

DESCRIPTION (provided by applicant): The objective of the training program in Basic Medical Research in Oncology at the University of Chicago is to provide an outstanding interdisciplinary research training environment for postdoctoral fellows who have completed a minimum of three years of postgraduate training in internal medicine (including at least one year in hematology/Oncology) in order to prepare them for academic careers in oncology. The Section of Hematology/Oncology offers a three-year ACGME training in hematology/oncology with the expectation that candidates for research training will complete one clinical year funded by the hospital and then have a minimum of two or three years of training under the proposed training grant. The direction of the program -- the integration of training in basic and clinical oncology has not changed since the program's inception but we have significantly enhanced our training in clinical research, cancer genomics, population and health services research in response to a national need. Unique structural elements in the training include: 1) access to a diverse population of cancer patients; 2) training under the guidance of multidisciplinary research preceptor (s) within project areas; 3) specific educational pathways in the form of course work and special seminars leading to a Master of Health Studies degree or Certificate; 4) service learning opportunities to reduce cancer disparities and inequities. The research training faculty preceptors interact on a number of collaborative research and training efforts. This interaction is fostered by the close proximity of the investigators at the University of Chicago campus and particularly by their research activities within our NCI-designated comprehensive cancer center. Generally, research programs fall into three distinct areas - patient-oriented research, translational/basic science and population science research. In the proposed training period, we shall continue the successful elements of the program and enhance the curricular offerings by providing coursework in emerging areas of translational research including bioinformatics, cancer genomics, comparative effectiveness, and global health. Our extensive inpatient and outpatient facilities will continue to promote a comprehensive clinical training experience, while our research laboratories will allow for the acquisition of basic science skills. In addition, our diverse population on the southside of Chicago and our Global partners will provide learning opportunities in community based research locally and at International sites. Physicians completing our training program will enter the oncology work force as socially responsible citizens who are prepared for global leadership in oncology and can advance novel interdisciplinary approaches to solve complex problems in cancer research. With the rapid pace of scientific advances and an aging population prone to cancer, a well trained academic oncology work force as proposed in this training program remains a wise investment for the nation. PUBLIC HEALTH RELEVANCE: The objective of the training program in Basic Medical Oncology at the University of Chicago is to provide an outstanding interdisciplinary research training environment for postdoctoral fellows who have completed internal medicine residency training in order to prepare them for academic careers in oncology. Physicians completing our training program will enter the oncology work force as socially responsible citizens who are prepared to advance novel interdisciplinary approaches to complex problems in cancer research and assume global academic leadership in oncology.

DESCRIPTION (provided by applicant): The University of Chicago (UC) has supported active clinical and basic research programs as well as community-based research into the epidemiology and socio-cultural factors that contribute to disparities in the incidence and expression of breast cancer in partnership with the University of Ibadan (UI) and the University College Hospital (UCH) for more than a decade. The proposed International Partnership for Interdisciplinary Research Training in Chronic Non-Communicable Diseases and Disorders across the Lifespan program will deepen research methods skills amongst trainees in clinical research and introduce an important research methods dimension consistent with the needs expressed by in country collaborators. The dimension of interest is an interdisciplinary approach, a lateral shift, whereby trainees receive distinct added research training in another health related discipline such as bioethics, biostatistics, behavioral science, cancer biology, clinical pharmacology and pharmacogenetics, economics, demography, epidemiology, health policy, human genetics, immunology, molecular pathology, and the social sciences,. This lateral shift will increase capacity amongst trainees at various career levels to develop relevan hypotheses, plan appropriate study designs, operationalize research findings, nurture collaborations between investigators of different disciplines and in some trainees potentiate considerable shifts in thinking and approaches to preventing and curing the diseases that most affect this region and continent. Prototype trainees would be those who at the end of the program have deepened her/his primary research training in the clinical field they are most familiar with and has leveraged new health related discipline research methods OR one who has shifted to a primary focus on health related discipline with Masters or PhD level training and focusing on a given clinical topic; both with the goal of conducting team based interdisciplinary research that leads to substantive improvements in practical prevention and treatment practices. By consolidating and reorganizing existing research capacity within UI, strategic African-US teams will increasingly become fully operational and expand upon research projects to develop truly shared interdisciplinary programs. Program areas of focus have been selected by the joint Ibadan and Chicago training advisory group, and are particular areas where the UC can provide research support. The training program in Cancer is now fully operational having trained more than 200 Africans in the past ten years and now will advance to train a projected 416 Africans in 1) other non-communicable disorders such as Sickle Cell Disease, Asthma/COPD and Indoor Pollution as well as Women's Health; 2) expand to additional training methodologies and health disciplines such as dentistry, nursing and ophthalmology; 3) expand to other emerging South-South collaborations such as a new Nigeria-Tanzania partnership fostered by UC and 4) expand to other African countries through the African Organization on Research and Training In Cancer and African Society of Human Genetics. PUBLIC HEALTH RELEVANCE: The University of Ibadan has the burden of history as the premier university in Nigeria to continue to provide leadership in the creation and deployment of knowledge for development. The proposed international partnership will allow Ibadan to realize its present vision of transforming into a postgraduate, research-driven university with focus on the development of translational research capacity and skills-set to meet the growing health needs of the country and the entire continent of Africa.

? DESCRIPTION (provided by applicant): The overall goal of the University of Chicago K12 program in Oncology is to produce the next generation of highly skilled academic Oncologists who are capable of designing and administering hypothesis-driven pilot/Phase I, Phase II and Phase III cancer therapeutic trials and observational studies. To do this, we have created a tightly structured and mentored education program within an academically rigorous training environment that prepares the most compelling applicants for careers in academic oncology. The program is anchored within our Comprehensive Cancer Center and led by Olufunmilayo Olopade, MD along with Everett Vokes, MD with strong support from an Executive Committee as well as Internal and External Advisory Committees. The Paul Calabresi K12 Scholars Program is our highly mentored, didactic coursework-intensive program, and hands on clinical research training which results in a Master of Science in Health Studies/Clinical Investigations. Leveraging resources across the University, we have created a set of integrated interdisciplinary courses in translational science that blends genomics, social sciences, community based, clinical- and bio-informatics, and population studies. In its 1st funding cycle, the program has been successful in recruiting 5 Medical Oncologists, 2 Surgical Oncologists and 4 PhD Scientists who obtain the broad research training and comprehensive experience necessary to conduct patient-oriented cancer therapeutic research in team research environments, and to focus their research endeavors on patient-oriented research. An explicit goal of this Paul Calabresi Scholars program, as with all training programs in our institution, is that its training opportunities and benefits will extend far beyond the relatively few scholars whose stipends it will provide. The program has had a transformative and global impact and is reaching into the larger global oncology trainee community in Chicago and to young oncologists from other countries who come to train at our Institution as Global Health Scholars. Thus, the benefit that accrues from the program's implementation is substantial.

? DESCRIPTION (provided by applicant): Rapid advances in genetic and genomic technologies have revolutionized our approach to cancer risk assessment, screening, prevention and targeted cancer therapies, heralding the era of precision healthcare. The introduction of affordable next generation sequencing (NGS) testing including multi-gene panels and whole exome or genome sequencing provides a wealth of data on both rare and common genetic variants. While these technologies enable personalized cancer risk assessment and cancer prevention, they also require novel approaches to genetic counseling, interpretation of results and responsible communication of this complex information. While professional education in the technology and application of genomics to clinical care is urgently needed especially for community practitioners and trainees, it is not readily available and there are no opportunities for hands-on case based learning. To address the changing landscape and provide evidence-based professional education, we propose a unique interdisciplinary yearly conference series to highlight clinical innovations in cancer risk assessment and prevention. The format will include state-of the art lectures, panel discussions, small breakout sessions for case based learning and poster presentations. Our overall goal is to improve the quality of cancer risk assessment and precision prevention approaches by providing an interdisciplinary educational forum in which to disseminate new knowledge in translational genomics and evidence-based clinical care of high-risk patients and their at risk family members. In addition to our leadership team, a conference advisory committee (CAC) composed of external members with exceptional expertise in cancer genetics, who will advise on the conference agendas and speakers. Each year, we will feature different invited faculty who are experts in their field to provide state-of- the-art lectures and participate in panel and case discussions. At each subsequent conference, we will address our specific aims by disseminating updates at the cutting edge of research and clinical developments in the field. To develop a learning community, we will curate Pedigrees with accompanying clinical information submitted by workshop participants and publish an annual conference Proceedings. Our target audience includes interdisciplinary health care providers for cancer patients (oncologists, gastroenterologists, gynecologists, primary care physicians and surgeons), nurses, physician assistants and genetic counselors from community and academic practices. By offering merit- and need-based travel awards, we will provide special opportunities for trainees, junior investigators, women and minorities to participate fully in the workshops and publish with senior mentors. The locations will alternate between downtown Chicago (2016, 2018 and 2020) and City of Hope in Duarte, CA (2017 and 2019). By tracking a number of metrics and due to the dynamic nature of the emerging field of Precision Healthcare, we will alter our conference agenda to accommodate new developments and remain up-to-date and relevant to clinical practice.

SUMMARY The proposed African Cancer Leaders Institute (ACLI) is a ?meeting within a meeting? designed to coincide with the biennial AORTIC conference, beginning with the forthcoming, ?Cancer in Africa: Making Strides, Creating Solutions? in Kigali, Rwanda, November 7-10, 2017. The ACLI will identify young clinical research leaders who are capable of leading interdisciplinary teams to improve cancer treatment in Africa. The long-term goal of the ACLI is to provide an intellectually stimulating platform to propel emerging global cancer leaders from Africa and the US to receive support for innovative cancer research in Africa, and to stimulate an African network for emerging leaders in cancer research in Africa. The ACLI platform will have annual goals and objectives set by the Education and Research Sub-Committees of AORTIC in collaboration with the ACLI program Organizers. The ACLI will widely solicit competitive applications from the US and Africa. Five emerging Leaders will be fully-funded for travel and participation in ACLI and the AORTIC conference. Five emerging Leaders from high-income countries with meritorious abstracts and application will be selected for Merit travel award in order to forge professional relationships and foster peer mentorship. Participants will attend lectures on best practices in developing a research career, identifying and developing cancer research projects, and disseminating research to a variety of audiences. Special sessions will be arranged for ACLI participants to discuss and evaluate the concepts presented at the AORTIC conference to enhance participants' learning and career development experience. All participants will have a chance to be mentored by Senior Leaders attending the main conference. Each ACLI participant will be asked to prepare a brief 15 minute overview of career accomplishments and plans for their career development activities as an emerging leader for cancer research in Africa. We will track a number of metrics including conference evaluations, career landmarks, publication records and the number of ACLI members who compete successfully for Africa focused K43 and K07 or K23 grants.

PROJECT ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT- CA-20-042. The ongoing pandemic of the coronavirus disease 2019 (COVID-19) is a public health and economic emergency that has disrupted the lives of breast cancer patients. Unfortunately, it has hit the United States heavily with more than 1.7 million people having been infected and more than 100,000 lives lost to date. While old age and having comorbidities are risk factors for dying from COVID-19, there is also a racial disparity in COVID-19 severity, with black and Latino patients in urban centers dying disproportionately from COVID-19. Breast cancer is the most common malignancy in women, with over 3.8 million women living in the United States with a history of invasive breast cancer. African Americans with breast cancer have an elevated risk of all-cause mortality and breast cancer-specific mortality. During the COVID-19 pandemic, it is important to understand the impact of SARS-CoV-2 infection and COVID-19 on breast cancer disease progression, care delivery, and survivorship including quality of life during and after the COVID-19 outbreak. In response to the needs of patients participating in our P20 funded UChicago Interdisciplinary Health Disparities SPORE and to address these knowledge gaps, we propose to engage with the Community by conducting an online survey, reviewing electronic health records, and searching the National Death Index to determine status of 3,059 breast cancer patients in the Chicago Multiethnic Epidemiologic Breast Cancer Cohort. The project has three specific aims: First, we will evaluate the extent of treatment interruption because of COVID-19 outbreak, and understand the utilization and satisfaction with Telehealth. Second, we will conduct a holistic evaluation of COVID-19 and mitigation efforts on loneliness, anxiety, stress, economic impact, and lack of resources among breast cancer patients. Third, we will estimate the coronavirus infection rate, severity and case-fatality rate of COVID-19, and identify factors associated with severity and case-fatality rate of COVID-19. For each aim, we will examine racial differences to understand whether COVID-19 has worsened previously identified mortality gap in the Cohort. The Supplementary Project will greatly enhance our SPORE P20 program by supporting additional interviews and follow-up of the cancer cohort members, and will generate necessary data regarding the impact of COVID-19 epidemic and lockdown on translational research to close the mortality gap in our proposed full SPORE application. These data are critical for guiding both community level interventions and health systems adaptation to support high-risk patients in the era of COVID-19.

PROJECT ABSTRACT- Administrative Core A SPORE in Breast Cancer was first funded at the University of Chicago in September 2006 to assemble, integrate, and create the intellectual and physical resources required to catalyze translational research and research training in breast cancer. Our Breast SPORE, as well as other SPOREs, was not refunded in 2011 at the peak of the financial crisis that led to shrinkage of the entire biomedical enterprise. At the University of Chicago, we nonetheless capitalized on the breadth, depth, and diversity of faculty scholars and resources throughout the University and Affiliate Institutions, and on large institutional and Cancer Center as well as CTSA financial investments, to sustain a transformative, energized, and self-improving home for breast cancer researchers. We now have the opportunity to plan a Full P50 SPORE application in Cancer Health Disparities (CHD) in 2020 through this P20 Planning grant. Following are key governing properties of the P20 that will enable its success and expansion into a full SPORE: The Administrative Core provides strong support to the Program Director and co-Leaders, Executive Committee, IAB (including the Advocates), and the EAB. The administration of the SPORE in CHD is planned to be highly efficient in utilizing both the expertise available within the Institution, and the resources of the EAB. The specific aims of the core are: Aim 1: Provide overall oversight of all P20 SPORE planning activities including Research Projects and Cores; Aim 2: Maintain authority and responsibility for all fiscal and budgetary matters; Aim 3: Facilitate communication throughout the SPORE program; Aim 4; Provide support for SPORE advocates within the Internal Advisory Committee; Aim 5: Sustain ongoing collaborative projects, identify new opportunities for Inter-Spore Collaborations and public-private partnerships and Aim 6: Ensure compliance with all institutional, governmental and NCI-specific regulations and requirements As the Administrative Core is essential for the optimal functioning of the P20 SPORE, it has been developed to ensure optimal utilization of resources, optimal communication between components, optimal monitoring and oversight, and effective, efficient decision-making. Drs. Olopade, Huo and Nanda, as co-leaders of the P20 are committed to effective and efficient functioning of the Core.

Project Summary/Abstract With the increasing complexity of cancer care, the rising numbers of diverse cancer survivors in the US population, and the increasing global burden of cancer, it is critical that Pritzker School of Medicine (PSOM) prepare a workforce trained to meet these challenges. Workforce for the continuum of care from risk assessment and prevention, early detection, treatment, survivorship and end of life care is interdisciplinary and inter-professional but medical education has remained compartmentalized. We aim to transform our approach to training medical students at PSOM for 21st Century cancer care by developing the Scholars in Oncology Associated Research (SOAR) program. In a new highly innovative 11-week intensive summer program for medical students, SOAR participants will learn fundamentals of cancer research along with interdisciplinary and interprofessional cancer care. The program will enroll twelve medical students each year, including four students who will conduct global cancer research at established UChicago Global partner sites. Each student will conduct interdisciplinary cutting-edge cancer research in with strong mentorship by established NIH funded investigators in our Comprehensive Cancer Center or the Center for Global Health. In addition, trainees will take part in formal instruction in responsible conduct of research, didactic lectures on the science of oncology, interdisciplinary tumor boards, research skill development and career planning activities as well as opportunities for career exploration, networking, and outreach that will increase their knowledge of cancer and motivate them to pursue further education and training for future careers as cancer researchers. Trainees will be supported by a tiered mentorship structure that includes Faculty Cluster Group Leaders who will be responsible for monitoring progress along milestones of completing their projects and lead peer mentoring sessions where they learn about each other's research. Using didactic sessions, experiential research training in diverse settings that represent the diversity of cancer research, and formal exposure to national and global leaders in oncology research across the care continuum, SOAR participants will have a greater appreciation for research training in the context of the interdisciplinary and interprofessional oncology care. With rigorous evaluation and planning, we will continue to improve SOAR and determine if SOAR participants show a greater propensity to pursue cancer research and/or pursue oncology as a career, as well as track long-term outcomes such as publications, grants, and entry into academic careers. The SOAR program aims to inculcate the next generation of cancer researchers with the desire to understand and improve quality of cancer care through pursuit of research intensive careers in Academia, Industry, Government or private Health Systems. SOAR will enable PSOM to maintain its tradition of excellence in preparing a diverse and highly skilled workforce to achieve the promise of precision oncology care and promote global health equity.

ABSTRACT Aggressive breast cancer disproportionately affects young women of African Ancestry across the Diaspora, who continue to die at an excessively higher rate from the disease than any other racial/ethnic group in the US. Building on our recent findings that women in Nigeria have high prevalence of tumors with homologous recombination deficiency signature, our goal is to perform in depth genomic analyses using well phenotyped tumors from Nigeria. We hypothesize that the genomic determinants of breast cancer subtypes are also molecular drivers of tumor progression and represent targets for interventions to improve clinical outcomes and close the mortality gap. Specific aims are: (1) Examine whole genomes of well-phenotyped tumor/normal pairs to identify somatic mutation signatures and subclonal architecture. Mutation signatures connect cancer mutational processes to both exogenous and endogenous risk factors. Combined with the whole- genome and whole-exome sequencing (WGS, WES) data from Nigerian breast cancer patients (100 WGS and 127 WES) and TCGA (84 WGS and 1008 WES), we will infer mutation signatures and conduct life history analysis to understand sub-clonal architecture of lethal breast cancers (Year 1); (2) Validate the distribution of somatic mutation signatures and identify risk factors associated with mutation signatures. We will perform WES of additional 500 tumor/normal pairs to validate diversity of mutation landscape and signatures in unselected breast cancer cases in Nigeria (Years 1-5). We will validate somatic mutation spectrum and signatures identified in Aim 1 and compare to data from publicly available datasets including the TCGA, ICGC, and in collaboration with the Carolina Breast Cancer Study (CBCS). We will examine association between mutation signatures, germline variants, molecular subtypes and breast cancer survival. By identifying causal links between genetic and lifestyle/environmental factors that promote aggressive tumor progression, the proposed studies will have direct pubic health impact on millions of women in the African Diaspora. (3) Examine tumor heterogeneity and clonal evolution of breast cancers by sequencing multiple regions of the tumors. Clonal architecture can be described through the clustering of variants with similar cancer cell fractions, and also by their geographical distribution, resulting in much greater resolution of subclonal architecture. We will perform multi-region (4 cores per tumor) WGS, RNA-seq and in-depth analysis of 36 tumors (18 HR- and 18 HR+) to describe genomic inter- and intra-patient tumor heterogeneity that may affect clinical outcomes (Years 1-5). We will examine differential expression levels, somatic fusion genes, and aberrant splicing patterns and correlate findings with tumor evolution to infer somatic events that drive tumor progression. This highly innovative research integrating Nigerian breast cancer researchers with the global research community has the potential to have a large and sustained impact on cancer control policies and the delivery of precision cancer care for the most lethal subtypes of breast cancer in all populations.