Ann Richmond, Ph.D.
More Information
The role of the inflammatory response in tumor progression
Dr. Richmond received her Bachelor of Science degree from Northeast Louisiana University, her Master of Natural Sciences degree from Louisiana State University and her Ph.D. in Developmental Biology at Emory University in 1979. She conducted postdoctoral research in Tumor Biology at Emory, and then joined the faculty there, rising to the rank of associate professor of Medicine before moving to Vanderbilt in 1989 as tenured associate professor of Cell Biology and Medicine and as a research career scientist at the U.S. Department of Veterans Affairs Nashville campus. She was promoted to full professor in 1995, and she was appointed professor and vice chair of the Department of Cancer Biology in 2000.
Dr. Richmond is internationally known for her research on chemokines, small “chemotactic” proteins that attract inflammatory cells. She was the first to demonstrate that a chemokine can regulate tumor growth. Her early research involved purification and sequencing of one of the first known chemokines, CXCL1, and her lab played a major role in characterization of the role of its receptor, CXCR2, in leukocyte trafficking, inflammation, angiogenesis, wound healing and tumor progression. She and her colleagues helped elucidate the role that inhibitor of kappa-beta kinaseβ (IKKβ), an activator of the transcription factor NF-κB, plays in chemokine expression and melanoma cell survival, suggesting that IKKβ may be a potential target for melanoma therapy. They also have shown that targeting the NF-kB/IL-6/STAT3 pathway is a rational strategy for treating angiosarcoma.
Dr. Richmond’s body of work -- more than 164 publications cited by other scientists more than 10,000 times – has shed light on how the inflammatory process, combined with other genetic and environmental factors, contributes to tumor progression and metastasis. A goal of her research is the advancement of “personalized cancer therapy” -- determining which genes are mutated or amplified in individual tumors and delivering drugs that specifically inhibit the activity of those genes. Antagonizing chemokine receptors may provide new therapeutic options. Toward that end, she and her colleagues are working to learn more about the effects of therapy on the tumor microenvironment, including the development of drug resistance.
The Richmond laboratory currently investigates the intracellular signals that are important in the tumor microenvironment and in the pre-metastatic niche to reduce the establishment of metastatic lesions. Recently, following basic discoveries on the pathways involved in melanoma progression, her group developed translational studies using patient derived xenograft models to explore new therapeutic approaches for melanoma. They demonstrated that combining aurora kinase A inhibitors with MDM2 antagonists markedly inhibit melanoma tumor growth, using patient derived xenograft models as well as immunocompetent mouse models. They have also shown that while targeted deletion of IKKβ in melanoma cells blocks mutant Ras mediated transformation, targeted deletion of IKKβ in myeloid cells leads to enhanced tumor growth and metastasis for melanoma tumors. Surprisingly, we have shown that systemic inhibition of NF-κB inhibits growth of mutant Ras driven melanoma tumors. She now plans to extend initial studies combining Aurora Kinase and MDM2 inhibitors to evaluate an even more promising combination therapy, CDK4/6 inhibitors and MDM2 antagonists. They will develop animal models and utilize in vitro and in vivo imaging techniques to characterize the mechanism by which antagonists of cell cycle combined with reagents that enhance apoptosis may synergize to improve treatment for cancer. Her laboratory has worked to determine how inflammatory signals from tumors induce the chronic and elevated expression of chemokines and/or their receptors to recruit leukocytes that enhance or inhibit tumorigenesis and metastasis. They are experienced in the characterization of leukocyte interaction with the tumor microenvironment and in identification of subsets of these cells within the tumor using FACS. Moreover, we are currently characterizing the role of a number of small molecule inhibitors that affect melanoma tumor growth and metastasis using patient derived xenografts. She and her group recently determined the role of CXCR4 in mediating estrogen independent growth and metastasis of breast cancer and have shown that inhibition of CXCR2 and CXCR4 can alter the leukocyte composition of the pre-metastatic niche. She has an outstanding group of collaborators and access to phenomenal infrastructure for acquiring patients, obtaining informed consent, tissue collection, patient follow-up, and access to patients in clinical trials.
Dr. Richmond also is deeply committed to education. She has mentored more than 50 undergraduates, graduate students and postdoctoral fellows. She served as assistant dean of Biomedical Research Education and Training from 2005 to 2010, organized the first Chemokine and Chemokine Gordon Research Conference, which remains enormously popular, and is the current past president of the Society for Leukocyte Biology.
Research Information
A major question we are trying to answer in my laboratory is "What is the role of the inflammatory response in tumor progression". We are studying the role of proteins that promote the migration of inflammatory cells into tissues. These "chemotactic" proteins can educate leukocytes to either stimulate or inhibit tumor progression. These factors can also stimulate the growth of the tumor and recruit blood vessels into the tumor to provide a continuous supply of nutrients to feed tumor growth. We have tested with a variety of pharmaceutical drugs that shut down the inflammatory process and alter the expression of genes that recruit inflammatory cells into the tumor microenvironment. We are also evaluating how to deliver therapies that teach the patient's leukocytes to fight the growth of the tumor and switch from a pro-tumorigenic to an anti-tumorigenic state.
We have also learned that this inflammatory process, combined with other genetic and environmental factors, contributes to mutations in genes that regulate the growth of cells. Some of these mutations make the cells capable of continuous growth and enable the cancer cells to spread throughout the body and grow in distant organs. By determining what genes become mutated or amplified in each patient's tumor and then providing therapies that specifically inhibit the activity of that mutated or amplified gene, we can deliver "personalized cancer treatment" that addresses the problem in that persons specific cancer. This works so much better than the "one size fits all" approach often used previously in chemotherapy. Recently we have determined that inhibition of aurora kinases induce tumor cells to undergo senescence and when we inhibit aurora kinases while at the same time activate the tumor suppressor p53 or the death receptor DR5, melanoma cells die and tumors regress. We are also interested in evaluating how therapeutic agents that target driver mutations such as PI3K, RAS or BRAF affect the tumor microenvironment and the immune response to the tumor. We postulate that in some instances drug resistance comes in part due to deleterious effects of the therapy on the tumor microenvironment. We collaborate with medical oncologists, surgical oncologists, bioengineers, cellular and molecular biologists, and scientists in pharmaceutical companies to address the scientific questions we are asking. This TEAM interaction enables us to optimize our studies to make important breakthroughs in tumor biology and tumor therapy. Our research is funded by the TVHS Department of Veterans Affairs, the National Cancer Institute, and the Department of Defense. I work with a wonderful group of postdoctoral fellows, students, and laboratory scientists who dedicate their lives to providing better treatments for cancer patients.
