Biomedical Base
Harvard Clinical Nutrition Research Center
Biomedical Base
Cancer Biology
Following are the primary investigators of this theme and a brief discussion of their work.
Dr. Willett continues to play a major role in the HCNRC renewal as an Investigator and Co-PI overseeing nutritional research activities between HMS and HSPH. He assumed the Chair of the Department of Nutrition at Harvard School of Public Health in 1991, becoming the Fredrick John Stare Professor of Epidemiology and Nutrition. He is also Professor of Medicine at Harvard Medical School An important part of the Department’s research and training activities in nutritional epidemiology are supported by a Program Project on Prospective Studies of Diet and Cancer, of which Dr. Willett is the Principal Investigator. This program provides the basic funding for a large prospective cohort study of men, the Health Professionals’ Follow-up Study, as well as the continued development and refinement of methods for assessing dietary intake in epidemiologic studies. The existence of this large study of men, as well as the Nurses’ Health Study and Nurses’ Health Study II, has created the platform for many other RO1 awards that allow examination of dietary factors in relation to numerous other diseases, including cardiovascular diseases, renal disease and nephrolithiasis, diabetes, Parkinson’s Disease, multiple sclerosis, and cognitive function. These large cohorts have been extremely productive of new and powerful information; in 2002 alone over 88 publications emanated from these studies. Dr. Willett was recently awarded the General Motors Mott Cancer Research Prize, and the Linus Pauling Prize for Nutrition Research and most recently the Bristol Myers Squibb Nutrition Research Award (2005) for his achievements in nutritional epidemiology. The coordinated effort between Dr. Willett at HSPH and Dr. Walker at DON and HCNRC provides an excellent forum for expanding clinical research and training in nutrition research within the Boston research community.
Edward Giovannucci
Dr. Giovannucci continues as an Investigator in the HCNRC renewal. Dr. Giovannucci’s primary research efforts focus on how nutritional, hormonal, and genetic factors are related to various malignancies, especially those of the prostate and colorectum. For prostate cancer, the work has centered on the role of specific antioxidants, particularly lycopene and selenium, and on the potentially deleterious effects of diets high in calcium and dietary fat. In addition to establishing risk factors, he has been interested in understanding etiologic mechanisms that will help provide a solid scientific rationale for preventive strategies. Specifically, he has studied how nutritional factors impact on prostate cancer through influencing levels of insulin-like growth factors and binding proteins, vitamin D metabolites, and steroid hormones. More recently, his work in this area includes how nutrients and hormones interact with genetic factors, including genetic variation in the vitamin D receptor, insulin-like growth factor receptor and the androgen receptor, in determining individual cancer risk. Regarding colorectal cancer, his work in the Nurses’ Health Study and Health Professionals Follow-Up Study has established specific modifiable risk factors that contribute to over 70% of colorectal cancers. An important component of the work for colorectal cancer has been the role of folic acid. He has reported on the importance of diets deficient in folic acid as a major risk factor for colorectal cancers and their adenomatous precursors in epidemiologic studies, and has also established a role for genetic polymorphisms of folic acid metabolizing enzymes, such as methylene tetrahydrofolate reductase, on cancer risk. Research in this area has been extended to a randomized intervention trial that Dr. Giovannucci is currently directing, in which the impact of folic acid supplementation on colorectal adenoma recurrence is being examined. By conducting a cost-effective randomized trial within the Nurses’ Health Study and Health Professionals Follow-Up Study cohorts, Dr. Giovannucci aims to establish a model for further chemopreventive interventions for colorectal adenoma recurrence.
Jin Rong Zhou
Dr. Zhou was a P/F awardee and Associate Investigator who now joins the HCNRC renewal as a new Investigator after obtaining RO1 support. His research in the Nutrition Metabolism Laboratory at Beth Israel Deaconess Medical Center investigates complex issues dealing with nutrition and health. His long-term goal is to identify bioactive dietary and nutritional components for the prevention and treatment of chronic diseases, such as cancer, obesity and diabetes. In order to test the efficacy of candidate components, he has established a series of clinically relevant animal models for chronic diseases, such as the cancers of prostate, breast, and bladder and obesity/diabetes. He has also applied advanced techniques for cellular and molecular biology and genetics/proteomics to elucidate the mechanisms of action of candidate bioactive components. By combining efficacy evaluation and mechanistic studies, he seeks to identify effective dietary and nutritional regimens for the prevention and treatment of cancer and/or obesity/diabetes.
Jose Halperin
Dr. Halperin joins the HCNRC renewal as a new Investigator. For the past 10 years his research has focused on translational regulation of gene expression in general and in cancer in particular. This research originated with the discovery of the anticancer effect of the anti-fungal drug Clotrimazole (CLT). He reported that CLT has a dual effect on intracellular calcium: it releases calcium from internal stores and closes restorative calcium influx. The resulting partial depletion of internal calcium activates the enzyme PKR, which phosphorylates and thereby inhibits eukaryotic initiation factor 2 (eIF2), the first step in mRNA translation initiation. In this manner, CLT inhibits translation initiation and synthesis of a subset of proteinsthat includes cyclin D1 and E, and stops cell cycle progression in the G1. The subsequent identification of the pharmacophore responsible for this anti-cancer effect of CLT has led to the rational design of proprietary analogs that are more potent and less toxic than CLT. He is currently the PI of a multi-center National Cooperative Drug Discovery Group (NCCDG) formed with NCI funding to discover inhibitors of translation initiation for cancer therapy. As part of this effort, his laboratory has now developed a facility for organic synthesis of small molecules and a state-of-the-art fully automated high throughput screening facility to test libraries of compounds (including nutrients) in mechanism-specific assays that he has developed. He has also established a mechanism-specific animal cancer model for in vivo screening of translation initiation inhibitors in pre-clinical development. His laboratory’s most recent finding is that the n-3 unsaturated fatty acid EPA exerts anti-cancer effects mediated by inhibition of translation initiation in a manner almost identical to the effect of CLT. Oral administration of EPA to mice bearing human cancer xenografts induces phosphorylation of eIF2, a biomarker of translation initiation inhibition, downregulates cyclin D1 expression, and inhibits tumor growth. These results are potentially important because epidemiological studies have shown that populations eating fish diets rich in EPA exhibit a very low incidence of cancer. He is currently conducting a clinical trial to analyze the effect of fish oil administration on the translation initiation biomarkers of prostate cancers; through this effort he expects to identify a cellular target and molecular biomarkers for the design of nutritional interventions for prostate cancer prevention.
Frederick Pei Li
Dr. Li continues as an Investigator in the HCNRC renewal. His research has historically focused on two main areas: inherited susceptibility to cancer, late effects of cancer in long-term survivors and the role of nutrition in its course. His studies of cancer prone individuals and families helped highlight the exceptionally high risk of cancer among genetically predisposed individuals. This led to the clinical description of Li-Fraumeni syndrome, and, subsequently, the identification of germline p53 mutations as the inherited defect in these families. Thereafter, his genetic research has been expanded to include hereditary retinoblastoma, breast cancer, melanoma and colon cancer. Concurrently, the occurrence of second primary cancers in predisposed families prompted Dr. Li to pursue studies of diverse late effects of cancer, including reproductive complications, dysfunction in vital organs and high risk of multiple neoplasms. In the last several years, Dr. Li’s research has shifted to include risk reduction, based on new knowledge of genetic and environmental (nutritional) causes of cancer. His recently funded studies include a smoking cessation project targeting survivors of childhood cancers. Data on a cohort of nearly 20,000 childhood cancer survivors indicates that approximately 18 percent are current smokers. His recently funded RO1 grant is using a telephone based counseling strategy to promote smoking cessation. In a second project, siblings of melanoma patients are being counseled to perform skin examination and seek dermatology consultation for early melanoma detection. The rationale is that siblings not only share sun exposure behaviors, but also genetic susceptibility factors. Dr. Li is also part of an international study of nearly 5,000 breast cancer families. He has received an R01 to perform genotype analysis on 2,000 of these cases. The second study of breast cancer is evaluating the Clinical Model of breast cancer genetic testing, as offered outside of academic centers. With IRB approval, 200 patients have been enrolled and will be followed for cancer occurrence and risk reduction behaviors based in part on diet.
Biographical sketch forthcoming.
Bruce Kristal
Dr. Kristal joins the HCNRC renewal as a new Investigator. He plans to join the Department of Nutrition at the HPSH this fall to develop metabolomics as a metabolic epidemiologic approach to the Nurses and Physician’s Health Study database. His expertise in metabolomics will add to the quality of nutritional epidemiologic studies within the Center. He has previously worked with Drs. Willett, Stamper, Sacks and Hu. He plans collaboration studies in the competing renewal application with Drs. Liu, Manson, Buring, Gillman and Zhou. He also plans to work closely with Dr. David Newburg, Director of the Cell Biology Core in using glycobiology as part of the metabolomics initiative. He will use the Cell Biology and Genomics Cores. As his metabolomics program develops he also plans to add his expertise to the Mass Spectrometry Core as an additional service for Center Investigators, Associate Investigators and P/F awardees.