COBRE Project - Specific Areas of Research
Inflammation and Cancer: The development of cancer is frequently preceded by a chronic inflammatory process triggered by an infectious agent (in the case of oncogenic viruses or bacteria), by pro-inflammatory carcinogens (e.g., cigarette smoke), by systemic dysfunction in immune regulation (e.g., in obesity) or by pre- malignant lesions. Among the components of the inflammatory stroma that support carcinogenesis are inflammatory cells, including myeloid-derived suppressor cells (MDSC) or tumor-associated macrophages (TAM) that promote angiogenesis, migration and invasion of malignant cells and metastasis. These stromal cells protect malignant cells from the effects of various chemotherapeutic agents or radiation and provide a supportive niche to tumor-initiating cells. The cells that form an inflammatory tumor microenvironment have been a primary focus of research supported by this COBRE, and will remain so in Phase III. Areas of research include:
- Identifying molecular checkpoints in the development and suppressive function of myeloid-derived suppressor cells (MDSC), tumor associated macrophages (TAM), and regulatory T cells (T-regs)
- Defining the role of oncogenes in promoting a pro-inflammatory microenvironment
- Identifying molecular mechanisms by which MDSC and TAM induce T and natural killer (NK) suppression
- Characterizing metabolic signatures of MDSC and TAM, a novel approach to understanding the tumor microenvironment, and defining a platform for the development of novel therapeutics to inhibit their immunosuppressive function
- Identifying novel molecular and metabolic biomarkers in TAM and/or circulating MDSC as a means to evaluate the inflammatory microenvironment in tumors and to predict the outcome in patients with cancer
- Conducting early stage clinical trials to assess the therapeutic efficacy of metabolic inhibitors of MDSC or TAM function, in combination with chemotherapy and/or radiation therapy in patients with cancer
- Evaluating arginase-1 in animal models as a novel therapeutic approach to the treatment of tumors and the prevention of graft vs. host disease in bone marrow transplantation
- Defining the role of the inflammatory micro-environment in the mechanism of action of investigational Notch inhibitors
Infection, Inflammation and Chronic Inflammation: Oncogenic viruses cause a chronic infection that results in chronic inflammation, which in turn promotes malignant transformation, prevents the development of a protective immune response, and protects malignant cells from the anti-tumor effects of chemotherapy and radiation. Such is the case with chronic infections with HPV, EBV and H. pylori. Our goal is to support research aimed at:
- Understanding the molecular mechanisms by which viruses initiate and maintain a chronic inflammatory response
- Determining the molecular mechanisms by which viral co-infections such as HIV and HPV, HPV and KSHV, and HIV and EBV cooperate to increase the chronic inflammatory process and/or enhance the malignant transformation of cells
- Comparing the inflammatory (immune) response of successfully vaccinated individuals with those who fail to respond to HPV vaccination.
- Defining the association of polyomaviruses with malignant transformation in colon cancer and Merkel cell carcinoma
- Determining the role of increased MDSC in HIV-infected patients, and the molecular mechanisms associated with cancer development
- Establishing early-stage clinical trials aimed at decreasing inflammatory cells as a means of enhancing anti-viral immunity.
The results of this research aim to develop strategies to prevent and/or inhibit the deleterious effect of chronic inflammation.
Obesity and Inflammation: A conjunction of conditions that promote health disparities. Obesity is well recognized as a pro-inflammatory condition that promotes the development of multiple diseases; therefore, understanding how it promotes a chronic inflammatory microenvironment is essential in developing preventive or therapeutic approaches to this problem. In addition, obesity and infection by oncogenic viruses and bacteria, such as HPV, H. pylori or HIV, are more frequent in the African American population in Louisiana and the surrounding states of Mississippi and Alabama. This provides a unique opportunity to develop translational, clinical, and population based research that may help identify biological mechanisms contributing to health disparities. It may also provide the basis for specific, culturally sensitive interventions in this community. This COBRE has been instrumental in promoting the development of such research through our partnership with the Dillard – LSU Center for Minority Health and Health Disparities Center, of which Dr. John Estrada is the Co-PI (P20MD004817). The next five years will allow us to develop joint research in the following areas:
- Molecular mechanisms by which the “metabolic syndrome” microenvironment converts normal granulocytes and macrophages into immunosuppressive MDSC.
- Molecular changes in the anti-viral response of immune cells cultured under “metabolic syndrome” conditions.
- Genomic and epi-genomic regulation of the inflammatory response in African Americans and Caucasians.
- Novel metabolic and checkpoint biomarkers of inflammatory cells in obese patients, as well as biomarker and metabolic changes with successful weight loss.
- Development of novel prognostic approaches to stratify risk in obese patients based on metabolic and inflammatory markers in peripheral blood cells.
These are some of the proposed areas of research, some of which we have ongoing projects supported by the Phase II of the COBRE and are generating preliminary data germane to the research questions posed above. New PJIs will be recruited through the Pilot Projects Program to expand into new areas of research.