KEVIN M. BROWN, PH.D., NCI-DCEG
Senior Investigator, Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute
Education: University of Virginia, Charlottesville, Virginia (B.A. in biology); George Washington University, Washington, D.C. (Ph.D. in genetics)
Training: Postdoctoral fellow, Genetic Basis for Human Disease Division, Translational Genomics Research Institute (TGen, Phoenix)
Before coming to NIH: Investigator, Integrative Cancer Genomics Division, TGen; adjunct professor of Genetic Epidemiology, Mayo Clinic Cancer Center (Scottsdale, Arizona); adjunct research assistant professor, Basic Medical Sciences, University of Arizona College of Medicine (Phoenix); adjunct professor, Molecular and Cellular Biology, Arizona State University (Tempe, Arizona)
Came to NIH: In 2010
Selected professional activities: Workshop faculty, American Association for Cancer Research’s Integrative Molecular Epidemiology Workshop; member, American Cancer Society’s Tumor Biology and Genomics Study Section
Outside interests: Mountain biking; barbequing
Research interests: My research focuses on the genetic underpinnings of melanoma susceptibility. My lab is identifying the genetic contributions and functional pathways associated with melanoma risk. Although early-stage melanoma is largely curable via surgical resection, outcomes for a significant proportion of late-stage melanoma patients remain poor despite considerable recent progress.
We are trying to gain a better understanding of the genetic factors contributing to melanoma risk so we can facilitate prevention and/or early-detection efforts in at-risk individuals. Also, we are actively involved in ongoing melanoma genome-wide association studies (GWAS) as members of the International Melanoma Genetics Consortium (GenoMEL) and the Melanoma Meta-analysis Consortium. We also work with GenoMEL member groups to use whole-genome and whole-exome sequencing approaches to better understand the genetics of melanoma susceptibility in melanoma-prone families. Lastly, we are also actively involved in ongoing renal-cell cancer GWAS at NCI, as well as meta-analyses with international teams working in the same area.
Beyond identification of novel risk genes and loci, a significant proportion of my research program focuses on functional characterization of cancer-susceptibility loci identified via GWAS. Although significant strides have been made in recent years toward cataloging loci involved in cancer risk, research into how these variants influence risk lags far behind. We are trying to better understand the molecular consequences of risk variants on gene regulation and function as well as the phenotypic effects of allele-specific gene functions. We perform fine-mapping of risk-associated regions, targeted and genome-wide expression analysis, gene-regulation and epigenetic work, and bioinformatic analysis of large genomic datasets.
Our current projects include a large-scale study of the influences of germline genetic variation on both gene regulation and cellular phenotypes in melanocytes and melanoma cells; functional genomic screens to identify genes that mediate phenotypes associated with early-stage tumor progression; large-scale reporter screens to identify risk-associated genetic variants conferring allele-specific gene regulatory potential; and directed analyses applied to specific susceptibility regions and genes.
NIDDK’s Biomedical and Metabolic Imaging Branch (BMIB)—which is made up of a multidisciplinary team of biomedical engineers, spectroscopy experts, and biologists—is using new chemical spectroscopic techniques to view organs (such as the liver, heart, and muscles) and improved imaging methodologies (that are faster and are at a higher resolution), and high-contrast techniques without the use of contrast agents.
We applied both computed tomography (CT) and magnetic-resonance imaging (MRI) for coronary imaging in the same patients. This approach allowed for identifying coronary abnormalities in people with HIV, Job syndrome, and Cushing syndrome. We also developed a new technique to image the coronary vessel wall—to characterize atherosclerotic coronary-artery disease—using high-magnetic-field MR scanners without the need for ionizing radiation. A patent application is pending for this new method, which could potentially be used to characterize and study coronary artery disease and its response to various lipid-lowering and anti-inflammatory therapies. These imaging techniques have also provided data for mathematical models that identify sites of maximum strain on the coronary arteries to predict points of potential atherosclerotic plaque accumulation and possible plaque vulnerability.
As part of the NIH obesity initiative, we have integrated the use of a large-bore high-magnetic-field MR scanner with a metabolic unit to characterize metabolic activity in people with a wide range of body-mass indices. An improvement and technical advancement in MR spectroscopy, developed by the BMIB team, has also been applied to measure fat and certain metabolites in the heart, liver, pancreas, and muscles and to correlate measurements with metabolic activity. We are also using imaging techniques that will allow for early detection and simultaneous quantification of liver fibrosis and inflammation in patients.
Research interests: My research focuses on the design, synthesis, and application of new small-molecule optical approaches for cancer diagnosis and treatment. A major emphasis has been to develop molecules that harness the unique properties of light in the near-infrared range. These wavelengths (between about 700 and 900 nanometers) are less absorbed by biological macromolecules, enabling applications in various in vivo settings. Our research is unique within the intramural program because we focus on the organic chemistry of fluorescent-probe molecules. In this work, we combine modern organic synthetic methods with physical and organic chemistry principles. This approach allows us to develop compounds with applications for both imaging and drug delivery in a range of challenging biomedical settings.
To enable modern imaging applications, scientists still need improved fluorescent probes. We have identified chemical reactions that facilitate the efficient preparation of molecules that have excellent stability and optical properties. We are particularly focused on developing compounds designed for fluorescence-guided surgical resection of solid tumors, as well molecules that delineate sensitive organs such as the bile duct and ureter. Our novel dyes are also proving useful in super-resolution microscopy applications, where photon output and photostability are particularly critical.
Going forward, we are developing molecules that use even longer wavelengths (greater than 1,000 nm), which can enable in vivo imaging with exceptional resolution at significant tissue depths.
In the area of drug delivery, we have developed some of the first single-photon photocaging reactions (activating molecules with light) that use near-infrared light. In our most significant effort, we are studying and using the photo-oxidative reactivity (oxidation reactions induced by light) of heptamethine cyanines (fluorescent dyes), reactions previously only associated with fluorophore photobleaching and photodegradation. We are combining this approach with antibody targeting methods to develop a general strategy for in vivo drug delivery. Going forward, we are identifying new chemistries that will enable the rapid and targeted release of chemically diverse biological stimuli.
We are also interested in using thymus-targeting and reconstitution strategies to improve T-cell differentiation after HSC transplantation. HSC transplantation is almost always performed by the intravenous administration of autologous or allogeneic HSCs. In the context of T-cell differentiation, it is presumed that the injected progenitors first home in on the bone marrow, and then some migrate into the thymus. The kinetics of this migration, as well as the length of time during which progenitors continue to enter the thymus after transplant, is still the subject of intense research efforts. Research from our group and others has shown that the direct intrathymic injection—rather than intravenous administration—of hematopoietic progenitors promotes a more rapid and robust thymopoiesis.
In our future studies, we aim to develop thymic-based strategies that target both hematopoietic progenitors and the diverse thymic stromal environment. Our goal will be to enhance T-cell regeneration and function after HSC transplantation.
I contracted malaria myself as a child growing up in Nairobi; that experience spurred my interest in studying malaria and other infectious diseases of global importance.
At NIH, my lab and I are defining how the survival processes of the malaria parasites (Plasmodium falciparum and P. vivax) are mediated and how they can be exploited for preventative, therapeutic, and diagnostic purposes. This work has direct implications for drug and vaccine development. We use the tools of microbiology, cell biology, biochemistry, biophysics, and structural biology to study proteins and complexes.
In particular, we are studying host-pathogen interactions in malaria in hopes of exploiting them to prevent disease; defining the mechanisms of how antibodies neutralize malaria parasites; and designing and engineering vaccines to protect against the disease. Recently, we described how the P. vivax Duffy binding proteins bind to red cells, and how antibodies prevent this interaction and neutralize malaria parasites. We have leveraged this information to design novel immunogens for P. vivax vaccines.