Duke Cancer Health Disparities (DCHD) P20 SPORE Program
Duke University
Principal Investigator(s):
Steve Patierno, PhD
- Principal Investigator(s) Contact Information
- Overview
- Project 1: Race-related RNA splicing in non-small cell lung cancer: Functional interrogation and therapeutic targeting
- Project 2: Racial differences in host immune response and gastric carcinogenesis: Translating underlying biology to promote gastric cancer interception
- Administrative Core
- Biospecimen/Pathology Core
- Biostatistics and Bioinformatics Core
- Developmental Research Program
- Institutional SPORE Website
Principal Investigator(s) Contact Information
Steve Patierno, PhD
Professor, Departments of Medicine, Pharmacology and Cancer Biology, and Family Medicine and Community Health
Deputy Director, Duke Cancer Institute
Duke University
20 Duke Medicine Circle
Durham, NC 27710
(919) 613-5093
Overview
This Duke Cancer Health Disparities (DCHD) P20 SPORE application evolved from efforts to address the complex problem of cancer health disparities and cancer disparities research spanning multiple levels and driven by complex interplay between social, psycho-social, lifestyle, environmental, structural, and biological determinants of health. Our OVERALL GOAL is to develop or improve new or existing interventions and therapies through a better understanding of cancer disparities prevalent in the Duke Cancer Institute (DCI)’s catchment area. We currently provide the infrastructure and resources to conduct innovative translational research to reduce cancer disparities through four projects focused on under-studied disparities (Aim 1); ensure availability of expert support through Administrative and Shared Resource Cores (Aim 2); seed Developmental Research Program (DRP) projects and grow the cancer disparities research community (Aim 3); and participate in and lead inter-SPORE activities that enhance our collective impact (Aim 4). The objectives of Project 1 are to extend this novel area of inquiry for precision oncology in NSCLC disparities by 1) examining DSGs and DEGs in an expanded cohort of clinically relevant NSCLC subgroups annotated for survival and smoking status, 2) functionally characterizing prioritized race-related alternative RNA splicing events, and 3) drugging prioritized race-related alternative RNA splicing events for therapeutic application. Project 2 lays the foundation for the creation of a population-based precision prevention strategy to reduce disparities in stomach cancer through targeted H. pylori eradication. The DRP recently identified two pilot projects for funding: a) Project 3 addresses the urgent need to interrogate molecular mechanisms driving the disparity in inflammatory breast cancer biology in African American and identify biomarkers that can be used to improve early and accurate diagnosis and b) Project 4 aims to understand how gene expression changes in discrete compartments (i.e. tumor versus tumor immune microenvironment) will significantly aid in furthering our understanding of racial disparities on a biologic level. The expected outcomes of this SPORE are to conduct and expand groundbreaking research in cancer health disparities, mitigate cancer disparities, and prepare for a DCHD P50 SPORE application.
Project 1: Race-related RNA Splicing in Non-small Cell Lung Cancer: Functional Interrogation and Therapeutic Targeting
Project Co-Leaders:
Jennifer Freedman, PhD (Basic Co-Leader)
Jeffery Clarke, MD (Physician Co-Leader)
Lung and bronchus cancer is the leading cause of cancer-related deaths in the United States and worldwide, with blacks having the highest number of deaths. Biological drivers of non-small cell lung cancer (NSCLC) in patients of African ancestry remain underexplored, with only a small number of studies on race-related differences in actionable mutations and aggregate gene expression. The proposed work addresses the urgent need to functionally characterize and therapeutically target novel race-related RNA splicing targets in NSCLC. We are the first team to identify alternative RNA splicing differences in NSCLC between patients of African and European ancestry. Specifically, in lung squamous cell carcinomas (LUSCs), the number of race-related differentially spliced genes (DSGs)(4,830) far exceeded the number of genes exhibiting race-related differential aggregate gene expression (DEGs)(267) in the same tissues. Among the DSGs, 17% are reported to be oncogenes, tumor suppressor genes and/or drivers and 355 RNA splicing events within DSGs are associated with LUSC survival. Among the DEGs, 6% are reported to be cancer-related and 18 are associated with LUSC survival. Furthermore, we have mined the National Cancer Institute Genomic Data Commons (NCI GDC) and have identified DSGs and DEGs in additional LUSCs as well as lung adenocarcinomas (LUADs). The objectives of the proposed work are to extend this novel area of inquiry with significance for precision oncology in NSCLC disparities by 1) examining DSGs and DEGs in an expanded cohort of clinically relevant NSCLC subgroups annotated for survival and smoking status, 2) functionally characterizing prioritized race-related alternative RNA splicing events, and 3) drugging prioritized race-related alternative RNA splicing events for therapeutic application. We propose three aims. Aim 1: Assess the expression of RNA splice variants and genes encoding trans-acting splicing factors across clinically relevant NSCLC subgroups in patients of African and European ancestry. Aim 2: Interrogate functional significance of prioritized race-related RNA splice variants for the biology of NSCLC. Aim 3: Develop novel splice-switching oligonucleotide (SSO) morpholino drugs to modulate RNA splicing events critical to race-related NSCLC for therapeutic application, and identify available targeted therapeutic agents that inhibit race-related NSCLC based on RNA splicing pathway(s).
Project 2: Racial Differences in Host Immune Response and Gastric Carcinogenesis: Translating Underlying Biology to Promote Gastric Cancer Interception
Project Co-Leaders:
Meira Epplein, PhD (Population Co-Leader)
Katherine Garman, MD (Physician Co-Leader)
The incidence of gastric cancer is responsible for the third largest disparity between Non-Hispanic African Americans and whites. More importantly, African Americans are more than twice as likely to die from gastric cancer than whites. Most gastric cancers are caused by Helicobacter pylori (H. pylori) infection, which is more common among African Americans than whites. Currently, little is known about how racially mediated differences in response to H. pylori infection might result in increased gastric cancer risk. H. pylori virulence factors such as cytotoxic-associated geneA CagA and more virulent forms of vacuolating cytotoxin A, VacA, interfere with the host adaptive immune system to allow H. pylori colonization in gastric mucosa. Our own preliminary data demonstrate that African Americans have increased antibody responses to CagA and VacA, which correlate with increased risk of metaplasia and dysplasia. Additional knowledge is still needed regarding race and other gastric cancer risk factors, such as PD-L1+, a CagA-dependent process found in 40% of gastric cancers and associated with decreased survival. The mechanisms through which race-associated genetic factors, such as IL-1β polymorphism (African Americans are at increased risk of harboring an IL-1β polymorphism associated with increased risk of gastric IM and dysplasia), relate to other virulence factors in the progression of precursor lesions and the pathogenesis of gastric cancer remain knowledge gaps to be addressed. Our goal is to address these gaps and translate biologic findings into new screening and surveillance strategies for clinical practice in order to address racial disparities and improve survival related to gastric cancer. We are creating a retrospective cohort to assess racial differences in FFPE tissue-based immune response along the gastric carcinogenesis cascade (Aim 1); and prospectively comparing racial differences in host response to H. pylori in fresh serum and tissue samples (Aim 2). Our translational approach will incorporate H. pylori virulence factors and the immune-based signature found in high-risk African Americans, which can then be tested in a future P50 SPORE proposal in order improve gastric cancer screening, surveillance, and prevention.
Administrative Core
Core Director:
Steve Patierno, PhD
The Administrative Core is responsible for organizing and supporting four full translational research Projects; two Shared Resource Cores; a Developmental Research Program (DRP); and a Pre-CEP (Career Enhancement Program, supported by institutional resources), as the forerunner of our future P50 CEP. In addition, the Core is responsible for transition planning for this P20 to compete for a full P50 SPORE grant. The Core provides leadership, coordination, oversight, infrastructure, and support personnel to facilitate administrative management; promote integration, communication, and collaboration; ensure fiscal and regulatory compliance; and oversee data operations, scientific rigor, and research progress. Steven Patierno, PhD, contact PI of this SPORE, leads this Core and receives expert advice, assistance, and guidance from three oversight bodies: an Executive Committee (EC) of all Project Leaders, and Core and Program Directors, as well as Internal (IAB) and External Advisory Boards (EAB), both of which include patient advocates. The team also benefits from an experienced Administrator, and professionals with extensive fiscal and regulatory compliance experience. The Specific Aims of the Administrative Core are to provide administrative management and oversight (Aim 1); provide financial management and ensure compliance with fiscal and research policies (Aim 2); provide oversight of all data operations (Aim 3); promote integration within the SPORE and the Institution Aim 4); provide scientific management to evaluate Program and research progress (Aim 5); and plan transition to a full P50 Cancer Disparities SPORE (Aim 6). The Core monitors research progress and productivity, scientific rigor and transparency, and effective use of Shared Resource Cores. With the EC, the Core leads strategic planning and implementation of activities to prepare this Program’s competitive P50 application; develops and implements strategies to address progress, plans, challenges, and solutions, including initiation of formal processes to replace Projects when needed; and evaluates DRP Project proposals. This Core also connects with quality assurance oversight provided by Duke Office of Regulatory Affairs and Quality. Finally, through formal evaluation processes involving an external evaluation contractor, the IAB and EAB, the Core facilitates assessment of all activities and implement recommendations, guidance, and direction to enhance success.
Biospecimen/Pathology Core
Core Director:
Shannon McCall, MD
The Biospecimen/Pathology Core is housed in the Duke Cancer Institute’s BioRepository & Precision Pathology Center (BRPC). The BRPC is a Shared Resource of the Duke Cancer Institute and supported in part by the Duke Cancer Center Support Grant (5P30-CA014236-45). This NCI-funded shared service center obtains broad consent from patients for blood and tissue sample donation and procures, processes and banks both liquid and tissue biospecimens, supports Duke’s “living biobank” with the Duke Patient-Derived Xenograft and Primary Tumor Cell Culture Services, and implements bioinformatic and clinical strategies for precise sample and model annotation. The Core efficiently provides high-quality tissue, blood and fluid-based biospecimens and processing services to requesting investigators, and continues to adjust practices as researcher needs evolve (Aim 1); supports current and future DCHD P20 projects through expansion of existing best practices in tissue procurement, processing, and sample management (Aim 2); and educates the local, regional and national community on the importance of available biospecimens in biomedical research to enhance availability of specimens and data from underrepresented minorities (Aim 3). The Duke BRPC has recently been awarded an NCI UM1 to join the Cooperative Human Tissue N Network (CHTN) (www.chtn.org); this network of biorepositories supports deeper cohort generations from across the country. For the current Research Projects, we provide appropriate lung cancer specimens and associated data from multiple races/ethnicities (Project 1), and stomach biopsies positive for H. pylori from Black patients (Project 2). Given the BRPC’s existing library, a recent focus on underrepresented minority inclusion and CHTN participation, a wide range of cancer disparities research should be possible. This Core serves Projects 1-4 and meets the needs of approved Pilot Projects. Dr. McCall provides updates on Core activities and remains up to date on Projects’ needs.
Biostatistics and Bioinformatics Core
Core Directors:
Terry Hyslop, PhD
Kouros Owzar, PhD
The mission of the Biostatistics and Bioinformatics Core is to provide support of cancer health disparities research in the Duke Cancer Health Disparities (DCHD) P20 SPORE program. The Core serves as a centralized resource for expertise in applied and theoretical cancer biostatistics and bioinformatics, data science, machine learning, and scientific computing. The Core mission is accomplished within the framework of sound data provenance and statistical principles, literate programming, and reproducible analysis. The code to reproduce analyses is tracked using source code management software and disseminated publicly. Any software extended or developed de novo by this Core will be disseminated to the cancer research community with adequate documentation and under a free public license. Core 2 provides basic, clinical, and translational cancer biostatistics and bioinformatics support (Aim 1); evaluates statistical and computational methods and tools (Aim 2); and provides consulting and education to support current and future DCHD P20 projects (Aim 3). The Core provides cancer biostatistics and bioinformatics expertise in support of the research conducted by Projects 1-4. This will ensure that the projects have clearly stated quantitative objectives, comprehensive data quality control plans, and clearly defined interim and final analysis plans using appropriate statistical and computational methodology, and computing infrastructure. For Project 1, the Core has provided the statistical design and analysis plan for the proposed cluster randomized design and provides statistical support from the recruitment to the final analysis stage. For Project 2, the Core provides RNA sequencing analysis support from initial quality control assessment of raw reads and pre-processing, to downstream statistical analysis and annotation. Core personnel actively collaborate with Core 1 in the sequencing design. Core leaders actively consult with and educate program investigators, as well as the DRP and Pre-CEP awardees. The Biostatistics and Bioinformatics Core serves all Projects, consults and works with DRP and CEP awardees, is represented on the Executive Committee, and works closely with the Biospecimen/Pathology Core and the Administrative Core. Our services are crucial to achieving the shared goals of the DCHD P20 SPORE.
Developmental Research Program
Program Directors:
Kathryn Pollak, PhD
Gerard Blobe, MD, PhD
The Developmental Research Program (DRP) is a critical component of the Duke Cancer Health Disparities (DCHD) P20 SPORE, supporting pilot research projects with translational potential relevant to cancer disparities and the participation of experienced investigators from other fields to work in translational cancer research. The DRP specifically targets projects that have a strong likelihood of developing into full SPORE projects, can be leveraged for funding as part of our planned DCHD P50 SPORE application, or can be developed as independent research projects. The efforts of the Co-Directors ensure a proactive DRP that prioritizes impactful pilot projects and faculty recruitment, and is well integrated into the overall SPORE. The DRP identifies and supports meritorious basic, translational, population, or clinical research projects that have a high probability of impacting cancer disparities (Aim 1); attracst outstanding new and/or experienced investigators, currently not working on cancer disparities, to pursue cancer disparities research (Aim 2); facilitates collaborative translational research to test novel concepts and paradigms relevant to cancer disparities in diagnosis, treatment or prevention (Aim 3); and evaluates progress on funded projects and facilitates their evolution into full SPORE projects or into independently funded projects (Aim 4). To accomplish these Aims, the DRP will award $100,000 each year ($50,000 from grant and $50,000 from institutional support) to fund at least one promising project per year. The awardees will be eligible for renewed funding for one additional year. All DRP applications will undergo a transparent multi-tiered peer review process involving the DRP-SRC, IAB, and EAB. DRP awardees are required to present progress reports on their projects at the bi-weekly EC meetings. To solicit investigators to apply for DRP awards, we use direct solicitation of members of the Duke Cancer Institute and of all clinical and basic science departments of the Duke School of Medicine, and Duke University. In addition, cancer disparities research programs at other institutions nationwide are contacted and advertisements placed in appropriate clinical and scientific journals to attract collaborative applications from outside of Duke. Special attention is given to promoting participation of women and minorities.