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Translational Research Center in Lung Cancer Disparities (TRACER)

Virginia Commonwealth University
Massey Cancer Center

Projects

Title: Comparing Exposure to Environmental Stress and PRMT6 Expression as Lung Cancer Risk Factors in Black Men

Project Co-Leaders:
Patrick Nana-Sinkam, M.D.
Robert A. Winn, M.D

Lung cancer remains the leading cause of cancer mortality in the United States with a projected estimate of 228,820 new cases and 135,720 deaths in 2020. Nationally, non-Hispanic African American/Black men have a disproportionately higher incidence and rate of death from lung cancer compared to their non-Hispanic White male counterparts; however, no such lung cancer disparities exist between African American/Black and white women nationally. Notably, the increased rates of lung cancer mortality seen in African American/Black men relative to their white male counterparts appears to be independent of smoking duration, intensity, quit years and socioeconomic status. These disparities are likely driven by a complex and poorly understood interaction between inequities in access care, segregation, upstream determinants of health, chronic exposure to community stress, tobacco exposure and molecular oncogenic drivers.

We have identified protein arginine methylation as a potentially exciting novel lung cancer biomarker and potential drug target, protein arginine methyl transferases 6 (PRMT6). We have determined that:

  1. PRMT6 expression is increased in African American/Black men;
  2. Smoking stimulates PRMT6 expression; and
  3. PRMT6 overexpression in an in vivo model drives lung tumor development.

We hypothesize that the combined effects of community stress and smoking in African American/Black men may be contributing to the African American/Black male “Smoking Paradox” and that PRMT6 may serve as a suitable biomarker capturing these combined exposures with the potential benefit of enhancing early detection of lung cancer in African American/Black men. This project aims to measure the interaction between the “community-ome” and the molecular determinants of lung cancer to better define the risks among African American/Black men. Gaining a better understanding of PRMT6 and its role as a molecular biomarker is an important first step to establishing this innovative approach. As such, it has become clear that the addition of molecular biomarkers (e.g. PRMT6 among others) could potentially improve the effectiveness of lung cancer screening. The findings from the proposed studies are expected to not only make significant contributions to the basic understanding of lung cancer health disparities in African American/Black men, but also assist in developing novel biomarkers for early detection of lung cancer in African American/Black men.

Table

Title: Biological Pathways in Stress Reactivity and Nicotine Addiction among African American/Black and White Smokers

Project Leader:
Chanita Hughes-Halbert, Ph.D.

Illustration

Even though smoking cessation is the best preventive strategy for reducing lung cancer risk and addressing racial disparities in outcomes, many smokers are unwilling or unable to make a quit attempt, and among those who try to quit smoking, utilization of evidence-based treatment is poor, especially in racial minorities. Stress relief, and the avoidance of adverse psychological and physiological reactions, are among the primary reasons for smoking initiation, maintenance and relapse in all populations; there is an established relationship between perceived stress and smoking behaviors from observational studies. However, stress responses have both psychological and physiological consequences that are important to smoking behaviors and cessation outcomes. Despite the significance of the HPA-axis pathway for both stress responses and nicotine addiction, racial differences in physiological stress responses have not been examined between African American/Black and white smokers. Under the leadership of an expert transdisciplinary investigative team that is supported by critical cores and shared resources for community engagement, biospecimen collection, storage, and processing and biostatistics and bioinformatics in the Translational Research Center in Lung Cancer Disparities (TRACER), Project 2 will be the first to examine racial differences in HPA-axis functioning between African American/Black and white male smokers to achieve the following specific aims:

  1. Examine racial differences in acute physiological stress responses between African American/Black and white male smokers using a laboratory model. The association between acute physiological stress response and tobacco-related behaviors will also be evaluated;
  2. Evaluate racial differences in daily cortisol patterns between African American/Black and white male smokers; and
  3. Identify factors that are important to acute and daily stress responses among African American/Black and white male smokers by examining acute and daily cortisol patterns based on exposure to chronic stressors. The relationship between acute and daily cortisol patterns, nicotine metabolism and nicotine dependence will also be explored among AA/Black and white male smokers.

Together with contextualized data on acute and chronic stress responses based on socioeconomic status, psychosocial and structural factors, Project 2 will generate novel empirical data that can be leveraged into precision strategies for lung cancer prevention through smoking cessation and other intervention approaches.

CORES

Core Leaders:
Robert A. Winn, M.D. (Leader)
Victoria Seewaldt, M.D. (Co-Leader)
Chanita Hughes-Halbert Ph.D. (Co-Leader)

The Administrative Core of this Cancer Disparities SPORE planning provides an essential framework for supporting the distinct features as well as the more routine administrative tasks associated with a large, multi-institution, multi-project and multi-core planning grant. It serves as Translational Research Center in Lung Cancer Disparities’ management entity, designed to engage a diverse cross-section of investigators representing lung-cancer focused and cancer disparities researchers, healthcare providers and community-based patient and public health stakeholders from three distinct geographic regions: Virginia, South Carolina and California. The core will be led by a team of Multi-Principal Investigators (MPIs), along with the guidance of an Executive Steering Committee, a Multi-Institutional Internal Advisory Board, an External Advisory Board and a Community Advisory Board. Together, the MPIs will leverage their distinct and complementary research and leadership expertise to oversee the day-to-day operations of TRACER as well as the shared governance structure to ensure proper oversight and coordination. They will oversee, coordinate and support all the activities for the proposed SPORE and provide the communication, integration, fiscal oversight, planning, evaluation and other required administrative functions to ensure all activities are well organized, documented and performed efficiently.

Core Leaders:
Charles Clevenger, M.D., Ph.D. (Leader)
Michael Idowu, M.D., M.P.H. (Co-Leader)
Loretta Erhunmwunsee, M.D. (Co-Leader)
John Pearce, Ph.D. (Co-Leader)

The TRACER Biospecimen/Pathology Core (BPC) will collect biospecimens from racially diverse lung cancer patients and individuals at high risk for lung cancer in support of cancer disparities research as well as provide a central data repository that links each specimen with essential histopathologic, clinical, molecular and social determinants of health data. The BPC will enhance TRACER supported investigations by factoring in multilevel determinants of cancer risk and outcomes.

Core Leaders:
Vanessa L Sheppard, Ph.D. (Leader)
Christopher Sistrunk, Ph.D. (Co-Leader)
Gayenell S. Magwood, Ph.D. (Co-Leader)

The Community Engagement Core (CE) incorporates tenets from an innovative Community-to-Bench framework to ensure the long-term impact of closing the gap in lung cancer disparities attributed to various factors that exist across the continuum from prevention to survivorship. Addressing these disparities requires a collaborative approach that integrates expertise of community residents and scientists. The overall goals of CE Core are to connect scientists and community stakeholders, translate and disseminate TRACER research findings, and co-develop innovative strategies to do this within the context of addressing lung cancer disparities.

Additionally, the Core, including community members, will educate investigators on how to employ community outreach and engagement (COE) into their research and provide training for the Biospecimen/Pathology Core that focuses on recruiting underrepresented groups to provide biospecimens and aid with incorporating community engagement approaches, recruiting participants and disseminating findings for the pilot research projects supported with the Developmental Research Program (DRP). Under the leadership of an experienced multidisciplinary team and in partnership with multiregional advisory boards, the CE Core will use evidence-based models of dissemination and implementation for the successful translation of research findings to effective interventions at the clinical and community level.

Core Leaders:
Dipankar Bandyopadhyay Ph.D. (Leader)
Russell Rockne, Ph.D. (Co-Leader)

The overall objective of the Biostatistics and Bioinformatics Core (BBC) is to serve as the focal point from which the TRACER investigators and career development candidates can draw the much-needed biostatistical, genomics and biomedical informatics expertise needed for proper planning and execution of their research projects. These services include assisting in experimental design, study plan development, hypotheses refinement, database integration and access, data quality control, sample size requirements and power calculations, analysis of the statistical design, development of randomization and stratification procedures, interim analyses, analysis of completed results (which includes both biostatistical and genomics analyses), presentation of research findings and scientific publication to disseminate new findings in the prevention and treatment of lung cancer.

Program

Program Leaders:
Victoria Seewaldt, M.D. (Leader)
Vanessa L Sheppard, Ph.D. (Co-Leader)

To ensure a focused pipeline of transdisciplinary research explorations into lung cancer disparities the Developmental Research Program (DRP) within this lung cancer disparities SPORE application aims to select and support highly promising and innovative pilot research projects to reduce health disparities in lung cancer. The TRACER MPI and DRP leadership have set clear priorities for the selection of pilot research projects. These priorities are:

  1. Projects demonstrating exceptional translational science potential;
  2. Projects inclusive of vertical and horizontal collaborations between the three participating institutions; and
  3. Projects with maximum impact on the diverse communities serving—Virginia, South Carolina, and southern California.

These pilot research projects may include basic research explorations using human samples, diagnostic or treatment clinical interventions in the form of clinical trials or community-based prevention interventions. The ultimate goal of the DRP is to establish a pipeline of research focused on the multi-dimensional causes of lung cancer disparities within the diverse populations served by the partnering institutions and to develop the preliminary data to support competitive research projects.