Spotlight On...

Thomas Kensler has long held a passion for discovery, initially as a mountaineer seeking first ascents and new routes in Alaska. Expeditionary climbing provided the template for teamwork, which formed the basis of his distinguished career in environmental carcinogenesis and prevention. In 2007, he received the AACR-American Cancer Society Award for Research Excellence in Cancer Epidemiology and Prevention for providing outstanding leadership to multidisciplinary teams of basic scientists, epidemiologists, biostatisticians and clinicians to the field of chemoprevention in a multicultural, international setting. He has led major initiatives to translate molecular targeting for chemoprevention into clinical trials for the reduction of liver cancer in highrisk populations, especially in China.

Hepatocellular carcinoma, or liver cancer, is one of the most common malignancies worldwide, with nearly 600,000 deaths annually, over one–half of which occur in the People’s Republic of China. Indeed, liver cancer is the leading cause of cancer death in Qidong, Jiangsu, PRC, a primary site for Dr. Kensler’s investigations. Infection with hepatitis virus and exposure to aflatoxins in the diet contribute synergistically to the risk of hepatocellular carcinoma. Aflatoxins are potent carcinogens produced by fungi and are consistent contaminants of the food supply in this area, particularly in corn, peanuts, soya sauce and fermented soy beans. Public health strategies for reducing the burden of liver cancer include vaccination programs against hepatitis B virus as well as reduced aflatoxin exposure and protection against its molecular actions.

In the 1980’s, Tom assembled a team of collaborators to develop quantitative experimental hepatocarcinogenesis models to evaluate the efficacy and mode of action of chemoprevention agents against aflatoxin. The key collaborations were initiated with John Groopman, Ph.D., now at Johns Hopkins University, and Bill Roebuck, Ph.D., at Dartmouth Medical School. This trio continues to combine biochemical and molecular studies with analytical chemical methodologies and experimental pathology to elucidate the molecular basis for protection against carcinogen-DNA damage and its resulting cancer initiation. From this work came the development of dithiolethiones as a class of chemopreventive agents, especially the evaluation of one such agent, oltipraz, in clinical chemoprevention trials.

Tom’s early research also helped to establish a role for reactive oxygen species in the tumor promotion process and provided early insights into the insidious nature of these oxidation reactions in carcinogenesis. This work has been thematically carried forward over the last 20 years and forms the basis for a number of molecular investigations that underpin chemoprevention. His collective work on oxygen radicals in tumor promotion has been highly cited and led to investigations of the role of antioxidants, as well as chemicals functioning as enzymes (called biomimetic superoxide dismutases) in protecting against free radical damage in this setting.

Tom's recent laboratory contributions have highlighted the importance of one cellular mechanism -- the Keap1-Nrf2 signaling pathway -- as a target for chemoprevention. This pathway appears to cut cancer risk through the induction of genes linked to carcinogen detoxication, antioxidative and anti-inflammatory processes. Collectively, these mechanisms protect the genome against carcinogens that bind to DNA and free radicals.

These findings not only have importance in cancer research, but have also been extended to the larger field of adaptive responses to environmental stresses that may lead to asthma, emphysema, and neurodegeneration.

The translation of preclinical studies to human chemoprevention trials requires basic scientific information for the selection of agents and development of biomarkers, coupled with public health guidelines that speed the delivery of appropriate interventions to at-risk populations. Clinical trials in China, in collaboration with the Shanghai Cancer Institute and the Qidong Liver Cancer Institute, together with George Bailey, Ph.D., of Oregon State University and Paul Talalay, M.D., at the Johns Hopkins School of Medicine, with chlorophyllin and glucosinolate-rich broccoli sprouts, respectively, are prototypes for food-based approaches to preventing cancer. These population-level interventions are both mechanistically grounded and highly practical. In fact, ongoing clinical studies in Qidong are demonstrating that such food-based interventions -- focused on Keap1-Nrf2 as a molecular target -- can lead to diminished DNA damage by aflatoxins in local residents.

Tom received a doctorate in toxicology at the Massachusetts Institute of Technology and continued his training with postdoctoral fellowships at the McArdle Laboratory for Cancer Research at the University of Wisconsin, and then at the National Cancer Institute in Bethesda, MD. In 1980, he joined the Department of Environmental Health Sciences at the Johns Hopkins School of Hygiene and Public Health as a Research Associate and quickly rose through the academic ranks. He is currently Professor of Toxicology in the Department of Environmental Health Sciences at the Johns Hopkins Bloomberg School of Public Health and he holds joint appointments in the Department of Biochemistry and Molecular Biology as well as in the Departments of Pharmacology and Molecular Sciences, and Oncology in the Johns Hopkins School of Medicine. He also holds several Visiting Professorships in China. He is currently a member of the NIH Chemo/Dietary Study Section and serves as the Cancer Prevention editor for the journal Carcinogenesis.

Kayaking now allows Tom a more sedentary means of enjoying the Arctic through extended journeys among the islands and coastline of Hudson Bay.