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Tobacco Investigators at Lombardi
Georgetown University Collaborators
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Home » ResearchTobacco Research at LombardiTobacco research at Lombardi spans behavioral, genetic, epidemiology, basic science and policy, with a specific focus on harm reduction. We adopt a transdisciplinary approach to the biobehavioral model for smoking behavior and harm. An important area of Lombardi's tobacco research is harm reduction as a method of reducing risk. Following are brief descriptions of the ongoing tobacco research studies at Lombardi.
ADHD and Smoking Dr. Kenneth Tercyak's translational tobacco research is supported by an NCI Research Career Development Award and examines smoking and other risky behaviors among children and adolescents seeking primary medical care, medical care for chronic illness, and medical care for attention-deficit/hyperactivity disorder (ADHD); a genetic component of this work explores genes thought to relate to tobacco use. The premise of this line of inquiry is that general and illness-specific stressors contribute to smoking among affected youth (despite smoking's well-known negative side effects on physical health), and that both smoking and ADHD symptoms are over-expressed among youth with dopamine transporter/receptor gene polymorphisms. Dr. Tercyak has found that, indeed, youth with ADHD symptoms are at high risk for smoking and that chronically ill youth are just as likely to smoke as their unaffected peers. The results of this work are expected to lead to targeted prevention and intervention programs to decrease tobacco use among high-risk populations. Behavioral Research in the National Lung Screening Trial The Lombardi Comprehensive Cancer Center is a national study site for both the Prostate, Lung, Colon, and Ovarian Cancer Screening Trial (PLCO) and the National Lung Screening Trial (NLST). Both trials address major research questions about screening for lung cancer in current and former smokers. The principle investigator for the PLCO and NLST trials is Edward Gelmann, MD. Matthew Freedman, MD, MBA, is lead radiology investigator for PLCO and principal co-investigator of NLST at Georgetown University. The PLCO Trial is closed to accrual, but has randomized 155,000 men and women to screening versus observation. Included in the screening arm is an annual chest X-ray for lung cancer detection. NLST addresses the risks and efficacy of a new approach to lung cancer screening, use of spiral computerized tomography (CT). Participants in this trial were randomized to annual chest X-ray or spiral CT examinations for 3 years. This trial is also closed to accrual and screening of 50,000 participants is ongoing at Lombardi and other centers a cross the country. Carcinogens in Human Lung Tissue Building upon Lombardi researchers' expertise in tobacco-related carcinogenesis and nicotine addiction, studies in the area of lung cancer have been increasing. These studies range from the detection of carcinogen and DNA damage in lung tissues to studies of radiation-induced lung cancer. While at the NCI, Drs. Radoslav Goldman and Peter Shields investigated the formation of DNA adducts in human lung tissue. This work is continuing but also is being expanded to improve both the exposure assessment and the cellular reactions in these autopsy donors. In collaboration with Dr. Edo Pellizzari of Research Triangle Institute, they have measured 11 polycyclic aromatic hydrocarbons (PAHs), known human carcinogens, in 70 lung tissue samples from cancer-free autopsy donors by gas chromatography-mass spectrometry. There were 37 smokers and 33 nonsmokers as estimated by serum cotinine concentration. The sum of PAH concentrations was higher in smokers (p = 0.01), and there was a dose-response relationship for greater smoking (p < 0.01). Smoking increased the concentration of five PAHs including benzo(a)pyrene, which increased approximately two-fold. The risk for increasing carcinogenic PAHs (odds ratio, 8.20; 95% confidence interval, 2.39-28.09) was three-fold compared with noncarcinogenic PAHs (odds ratio, 2.61; 95% confidence interval, 0.75-9.12). A higher concentration of PAHs was detected in the lung tissue of males, although the estimated smoking was similar in males and females. Race was not associated with PAH concentrations overall, but PAH concentrations appeared to be higher in African-American males than in any other group. Age was weakly correlated with an increase in fluoranthene and pyrene. The measurement of PAHs in human lung tissue can be used to estimate the actual dose to the target organ. It has more recently been determined that the level of cytochrome P450 Ia1 in the lung tissue correlates with the PAH levels. This work will now allow the investigators to relate the formation of DNA adducts to the actual carcinogen level in the target organ, as well as other cellular responses (e.g., p53 induction, estrogen receptor expression). Computer-Aided Detection In collaboration with the ISIS Imaging Science and Information Systems Research Center at Georgetown, the Lombardi Comprehensive Cancer Center is working to develop methods for the computer-aided analysis of chest radiographs and lung CTs for cancer. The studies have both corporate and National Cancer Institute funding. Three different types of computer tasks are under development: programs that will assist radiologists in the detection of lung nodules that could represent cancer, programs that will assist radiologists in determining whether a detected nodule is benign or malignant, and tools to assist radiologists as they interpret lung CT images by automating some of the tasks that they currently perform. This work is under the direction of Matthew Freedman, MD, from the Lombardi Comprehensive Cancer Center, and Shih-Chung Benedict Lo, PhD, from the ISIS Research Center. DNA Repair and Lung Cancer The primary focus of this study is to assess the risk associated with mutagen sensitivity. Drs. Christopher Loffredo and Peter Shields, in conjunction with Drs. Curtis Harris of the NCI and Anthony Alberg of Johns Hopkins University, are conducting a five-hospital case-control study in Baltimore, Maryland. Controls are recruited using Department of Motor Vehicles records. There will be 200 Caucasian and 200 African American cases, with the latter oversampled so that the investigators can assess racial differences in cancer risk. Thus far, individual sensitivity to bleomycin-induced chromosome breaks has been compared in 152 newly diagnosed and previously untreated lung cancer patients with 94 population controls and 85 hospital controls with no history of cancer. The mean number of bleomycin-induced breaks per cell was 1.01 for the cases compared with 0.86 for hospital controls (P<0.01) and 0.89 for population controls (P<0.01). The mean number of breaks per cell was 1.01 for those >65 years old and 0.81 for those <65 years old (P<0.01) among population controls. Defining "bleomycin sensitive" as greater than 0.84 break/cell (the median level in population controls), 66% of the cases were bleomycin sensitive compared with 46% of the hospital controls (adjusted odds ratio [aOR] = 2.69, 95% confidence interval [CI] = 1.33, 5.04), and 49% of the population controls (aOR = 2.18, 95% CI = 1.13, 4.21). When analyzed as a continuous variable, there was an approximately 14% increase in lung cancer risk with each unit (one unit = 0.1 breaks/cell) of increase in bleomycin-induced chromosome breaks, adjusted for age, gender, race and smoking history. These data indicate that the increased number of bleomycin-induced chromosome breaks is significantly associated with an increased risk of lung cancer in the first 331 subjects. Evaluation of Harm Reduction through Use of Modified Cigarette Products or Nicotine Replacement Therapy In 2000 and 2001, Dr. Peter Shields devoted an important effort to the activities of the Institute of Medicine's Committee for Assessing the Science Base for Harm Reduction. There, he conducted an extensive study of biomarkers and lung carcinogenesis in the context of establishing a quantitative dose-response relationship for smoking and cancer, and how one could assess the effectiveness of exposure reduction through the use of newly manufactured cigarette-like products or the use of supplemental nicotine replacement therapy in smokers. Integral to understanding harm reduction is the assessment of risk of low tar and full flavor cigarettes, such as the light cigarette, erroneously considered a harm reduction method in the 1960s. Genetics of Nicotine Addiction and Smoking Behavior: Transdisciplinary Tobacco Use Research Center (TTURC) The Transdisciplinary Tobacco Use Research Center (TTURC), awarded to Lombardi in 1999, spawned much of the center's tobacco-related research. The overall goals of the TTURC are to: 1) obtain a more complete understanding of the role of specific genetic factors and bio-behavioral mechanisms that promote tobacco use; and 2) apply this knowledge to the prevention, treatment and reductions of harm from tobacco exposure. In 2001, Dr. Lerman, PI of the TTURC, moved to the University of Pennsylvania. Several components of the TTURC remained here, including a project to investigate smoking genotypes (Dr. Peter Shields), a genetics laboratory (Dr. Peter Shields), and an investigation of the cost-effectiveness of alternative smoking cessation approaches (Dr. William Lawrence). The unifying theme for the TTURC is that there is a genetic basis to tobacco addition, cessation and smoking behavior, and that the genes governing such then affect carcinogenic outcomes. The initial basis of the TTURC was based upon a case-control study of smokers and non-smokers, and work on this study set continues today. Drs. Shields and Lerman initially reported in 1999 that genetic polymorphisms in the dopamine transporter gene and the dopamine D2 receptor gene predicted tobacco use and number of quitting attempts. They also reported that there was an interaction with depression and a genetic polymorphism in the dopamine D4 receptor, while a different allele was a risk factor in smoking and smoking relapse in African Americans. Also, a genetic polymorphism in the serotonin transporter gene affects people with higher neuroticism scores to increase smoking risk. Several other genes have been investigated, but no relationship to addiction was found. The current three TTURC projects examine the role of the above genes and others. The projects are designed to span the spectrum, from smoking initiation in adolescents to determinants of individuals' smoking amounts and how this affects DNA damage in the blood. The project based at Lombardi is carried out by Drs. Peter Shields, Christopher Loffredo and Radoslav Goldman. The aim is to determine if an individual's need to have a specific nicotine level is genetically controlled. It also will determine if genetic variability affects how people smoke (e.g., puffs per cigarette, depth of inhalation) and how this is related to the downstream formation of carcinogen-DNA adducts. The study is now in the field, where 200 Caucasian and 200 African American regular smokers are being recruited from the general population. Oversampling for African Americans will allow for the study of more typical smoking patterns within that group (i.e., menthol cigarette use). Dr. Shields also provides the molecular analyses for the off-site TTURC projects.
Molecular Epidemiology of Secondary Lung Cancer Risk Several studies indicate that women with breast cancer who undergo radiotherapy are susceptible to secondary lung cancer, whether or not they are smokers. However, all studies to date have had methodological limitations, have used crude estimates of radiation doses, and have included small numbers of individuals. Moreover, none have used molecular markers, which can improve exposure assessments and elucidate mediating mechanisms. In collaboration with Dr. Per Hall and coworkers at the Karolinska Institute, along with Dr. Timothy Jorgensen and Baljit Singh, Drs. Peter Shields and Bassem Haddad are studying this risk in detail by conducting a population-based study using the Swedish Cancer Registry (SCR). In this study, the investigators can provide accurate radiation dose estimates for the whole lung and also for each side of the lung (which incorporates an estimate of scatter) and will have reliable smoking data. Using the SCR and the unparalleled ability to obtain tissue blocks dating from the 1950s, Dr. Shields and colleagues have the unique opportunity to understand risk in the context of molecular markers, namely those that reflect p53 inactivation pathways (i.e., p53 mutations or loss of heterozygosity). Also, given that tumor blocks will be available for both the breast and lung tumors from the same women (proven to be useful even though dating back to 1958, see below), they also have the unique opportunity to study women who might be considered to have a phenotype of susceptibility to multiple primary cancers. The team obtained data from the SCR to estimate the risks of developing lung cancer in Sweden. From the SCR, 141,053 women had histologically confirmed invasive breast cancer as the first cancer reported between 1958 and 1997, and 613 of these had a subsequent primary lung cancer. A statistically significant increased standardized incidence ratio (SIR) of 1.32 (95% CI 1.22-1.43) for lung cancer risk was seen. During the first five years there was a significantly decreased risk, followed by significantly increased risks in the subsequent periods, reaching its maximum >20 years after breast diagnosis (SIR = 2.53; 95% CI 2.10 - 3.04). To study the potential impact of radiation therapy on the lung cancer risk, the predictive value of treatment to one breast was considered in relation to the side of the lung where the lung cancer subsequently occurred. There was a statistically significant concordance after more than 10 years after breast cancer diagnosis. Also, the team has been reviewing medical records and obtaining tumor blocks to evaluate p53 mutations, and has shown that they can successfully amplify p53 from 90% of the blocks, even those dating back to 1958. An extension of the p53 analysis is also underway with Dr. Frederica Perera of Columbia University to evaluate men in the Physician's Health Study. Dr. Perera already demonstrated that carcinogen-DNA adduct levels in the blood were prospectively predictive of lung cancer. The results from this study indicated that the men with GŪT transversions, thought to be related to smoking, also had the highest adduct levels (unpublished data). However, the number of study subjects examined was small and the investigators will replicate these activities when tumor blocks are collected for an updated cohort. Neuronal Nicotinic Acetylcholine Receptors Dr. Ken Kellar is studying nicotine receptors and how they relate to nicotine addiction. Dr. Kellar provided the first characterization of the brain receptor's pharmacological properties, brain region distribution and regulation. Subsequently, he has shown that these receptors also are increased in the brains of humans who smoke, indicating that the nicotine-induced increase in these receptors is an important consequence of smoking and suggesting it may be related to nicotine's addictive actions. He also published the first pictures (autoradiographs) demonstrating the effects of smoking on nicotinic receptors in human brain. In recent years, Dr. Kellar has developed new tools and methods, including radiolabeled epibatidine and antibody methods, which allow for the study of the characteristics and regulation of different subtypes of nicotinic acetylcholine receptors in the nervous system. In addition, he has created a library of stably transfected cell lines that express six different neuronal nicotinic receptor subtypes that are thought to serve normal physiological functions and that may be potential targets for nicotine's actions. Tobacco Research in Egypt Drs. Christopher Loffredo and Radoslav Goldman, in collaboration with researchers at the University of Maryland, were recently funded to develop a tobacco research infrastructure in Egypt. They will conduct two studies within a combined NIH/WHO tobacco research center for Egypt and the Middle East, a large program of research, community education and prevention, and policy studies. The research projects are: 1) an assessment of the attributable risk of cigarette and water-pipe smoking behaviors to lung, head and neck, and bladder cancers and; 2) a study of dopamine pathway genetic polymorphisms as mediators for tobacco addition, withdrawal, behavior and quitting success. Using the Internet to Disseminate Tobacco Dependence Treatment Reducing smoking prevalence requires innovative approaches to reach and treat current smokers. The Public Health Service (PHS) Guideline [3] recommends key components (behavioral coping, social support, pharmacological), greater intensity and combined delivery modes (telephone, self-help) as part of effective treatment. The Internet is an untapped resource that can potentially deliver proven cessation interventions to smokers. Little is known about what type of smoker uses the Internet, the components of Internet interventions that are most used, and what the mediators and moderators of effective use are. This study, being one of the first to evaluate the Internet, is focused on initial efficacy with an eye toward eventual dissemination. The Internet could have public health benefit as a cost-effective way to make an overall population impact. Tobacco Investigators at LombardiDr. Peter Shields: Dr. Shields is tenured professor in the Departments of Oncology and Medicine at Georgetown University. He is the Associate Director for Cancer Control and Population Sciences in the LCCC, and the Program Leader for Cancer Genetics and Epidemiology. Dr. Shields' focus of research is on gene-environment interactions for cancer risk and nicotine addiction. He develops and validates new biomarkers, both genotypic and phenotypic, and so his research includes the integration of basic science into epidemiology (molecular epidemiology). He has an established record for working with investigators at the Karolinska Institute. Dr. Shields serves on editorial boards of major journals such as Carcinogenesis and Cancer, Epidemiology, Biomarkers and Prevention. He was the first elected chair to lead the Molecular Epidemiology Group of the American Association of Cancer Research. In the area of Harm Reduction, Dr. Shields served on the IOM Committee and was the primary drafter of two chapters (11: Exposure and Biomarker Assessment and 12: Cancer). He also served on the NCI Tobacco Research Implementation Group, the NCI Lung Cancer Progress Review Group and the NIH Epidemiology and Disease-2 Study Section. Dr. Shields has led other highly integrated research projects. He was the PI of the Georgetown component of the PENN-Georgetown TTURC, and is the PI of a Department of Defense Breast Cancer Center of Excellence. Dr. Shields remains clinically active, practicing hematology and oncology. Thus, he has a diverse set of skills, and experience, for conducting transdisciplinary research. Dr. Jerry Rice: Dr. Rice is a Distinguished Professor of Oncology at the Georgetown University. He is an internationally recognized expert in experimental carcinogenesis and in carcinogenic hazard identification. During his 30-year laboratory and administrative career at the NCI, he published more than 250 research and review papers on tumor promotion (including the mouse skin system proposed in this application), identification of chemical carcinogens, transplacental carcinogenesis and the molecular pathology of human and experimental tumors. During his more recent career with the World Health Organization he directed the prestigious and internationally renowned IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. His accomplishments at the WHO include the 2002 Monographs review of tobacco smoke and involuntary smoking, in which cancers in five organ sites were newly recognized as attributable to cigarette smoking and environmental tobacco smoke was identified as carcinogenic to humans. Dr. Rice continues his involvement with the IARC Monographs program and will serve as chair of the working group to re-evaluate tobacco-associated nitrosamines and smokeless tobacco products in October 2004. Dr. Xiao Bin: Dr. Fung-Lung Chung: Dr. Chung's research focuses on the study of the mechnaisms of cancer induction by tobacco carcinogens and how we can use the knowledge gained to prevent lung cancer development by using chemopreventive agents. Dr. Saijun Fan: Saijun Fan, MD, PhD, joined Lombardi as an Associate Professor of Oncology in April 2003. Dr. Fan's studies are on the effect of nicotine and nicotine-derived nitrosamino ketone (a known lung carcinogen) on apoptosis induced by chemotherapeutic agents in lung cancer. The preliminary studies from his laboratory suggest that nicotine and NNK activate a Met-Akt-PAK1 survival signal pathway as a potential mechanism for their cytoprotection in lung cancer. These important studies may yield new strategies for the prevention and control of lung cancer related to smoking. Dr. Gary Filerman: Dr. Amanda Graham: Amanda Graham, PhD, is a clinical psychologist who joined Lombardi’s Cancer Control Program in 2006 with an appointment as Assistant Professor of Oncology. She received her PhD from the Chicago Medical School and following a clinical internship at the Yale University School of Medicine, she was a research fellow, then Assistant Professor at Brown University. Dr. Graham’s current research interest is developing innovative approaches to translate behavioral science into practice. She is principal investigator on an R01 grant that tests the effectiveness of a widely utilized Internet smoking cessation treatment (QuitNet) alone and in conjunction with an existing telephone quitline. Dr. Janie Heath: Janie Heath, PhD, APRN, BC-ANP, ACNP, is Assistant Professor, Director, Acute Care Nurse Practitioner and Acute & Critical Care Clinical Nurse Specialist Programs at Georgetown University. She has authored several data-based papers that focus on tobacco education in nursing and tobacco control policy papers. Currently she is the Director of the tobacco cessation program for GUMC where she does clinical practice, research, and community initiatives. Her primary research program involves the effect of the "Rx for Change: Clinician Assisted Tobacco Cessation Curriculum" on the self-efficacy of teaching tobacco cessation among nursing faculty and the clinical effect (helping patients quit) among healthcare providers who receive tobacco cessation training. Dr. Michael Johnson: Dr Johnson has considerable experience with transgenic models of carcinogenesis modes. He established and for several years directed the Georgetown University Transgenic Facility and had generated numerous novel transgenic models. He came to Lombardi as an ICI postdoctoral fellow to study the impact of endocrine therapy on mammary gland biology and carcinogenesis. He was appointed Assistant Professor in the Department of Pathology in 1993 and Oncology in 1999. Dr .Johnson has extensive experience with primary epithelial culture systems. Dr. Kenneth Kellar: Dr. Ken Kellar has studied neuronal nicotinic cholinergic receptors for more than 20 years. His lab initially characterized the pharmacology of brain nicotinic receptors that bind [3H]acetylcholine with high affinity, and he has since developed new, higher affinity and more selective nicotinic receptor ligands, including [3H]cytisine, [3H]epibatidine and [125I]epibatidine. His lab was the first to discover that repeated exposure to nicotine increases nicotinic receptors in rat brain. The Kellar lab was also one of the first to demonstrate that nicotinic receptors are located on dopamine axons, providing a direct mechanism by which nicotine can mediate dopamine release and thus activate reward pathways. Research in the Kellar lab is currently focused on understanding the structure, function and regulation of neuronal nicotinic cholinergic receptor subtypes in the nervous system. Dr. Kellar has over 100 publications and is an internationally recognized leader in this field. Dr. Christopher Loffredo: Dr. Loffredo is an Assistant Professor of Oncology and member of Lombardi's Cancer Genetics and Epidemiology Program. He received his PhD in toxicology, but performed most of his thesis work as an epidemiologist. He currently is a standing member of the NIH EPIC Study Section, and has RO1 funding from the National Cancer Institute to study gene-environment interactions using a case-control study design for hepatocellular carcinoma and non-Hodgkin's lymphoma in Egypt. Dr. Loffredo is an investigator in the PENN/Georgetown TTURC, where he is directing a project on genetics and smoking behavior measured by topography and biomarkers. There are over 200 subjects accrued to data. Dr. Robert Russell: Dr. Russell is Director of the Lombardi's Molecular Pathology Laboratory. He is a board certified veterinary pathologist, experienced in conducting animal model studies. He has experience with mouse skin painting model using tobacco smoke condensate and providing histological evaluation for pre-neoplastic and early changes in tumorigenesis. Dr. Stephanie Spernak: Dr. Spernak is an Assistant Professor of Oncology at Lombardi. She is a behavioral scientist and is currently coordinating the Quest clinical trial at Georgetown, under the direction of Joni Jensen and Dr. Hatsukami at the University of Minnesota. Dr. Kathryn Taylor: Dr. Taylor is an Associate Professor of Oncology and member of Lombardi's Cancer Control Program. An experienced clinical psychologist, Dr. Taylor has significant expertise in conducting cancer control studies, as the PI for 1) a multi-site, randomized intervention with breast cancer patients, 2) a randomized patient education intervention regarding prostate cancer screening, 3) an ongoing randomized trial of treatment decision making among men with early stage prostate cancer, and 4) a recently funded R01, a multi-site randomized trial regarding decision making and patient education for men considering prostate cancer screening. Dr. Taylor has tobacco-specific research experience as PI on an observational study in the NLST, an observational study of head/neck and lung cancer patients' continued tobacco use following diagnosis. She has examined tobacco use among African Americans and recent Haitian and Caribbean immigrants, has clinical experience in nicotine dependence treatment, and recently co-authored a review paper on smoking cessation interventions among cancer patients. Dr. Kenneth Tercyak: Dr. Tercyak is an Assistant Professor of Oncology and Pediatrics, the Director of Pediatric Psychology Research and Service in the Division of Pediatric Hematology-Oncology at Lombardi, and a member of the Cancer Control Program. He served as Project Director for an NCI Transdisciplinary Tobacco Use Research Center grant focused on the natural history of adolescent cigarette smoking. His primary research interests include the prevention and control of cancer/tobacco risks among youth, behavioral interventions to promote youth health, psychosocial oncology and genetic testing, and cancer survivorship. Dr. Tercyak holds a Career Development Award from the NCI focused on pediatric cancer/tobacco prevention and control and an R01 from the National Human Genome Research Institute focused on genetic testing outcomes; his work on cancer survivorship is supported by the Lance Armstrong Foundation. Dr. Yun-Ling Zheng: Dr. Zheng is an Assistant Professor in the Department of Oncology. Dr. Zheng has outstanding training in cancer genetics and epidemiology. She is board certified clinical cytogeneticist. Her work on using fluorescent in situ hybridization for prenatal genetic diagnosis and screening is widely recognized. She also has training in epidemiology and recently graduated from Johns Hopkins University, Bloomberg School of Public Health with an MPH degree. Dr. Zheng participated in several molecular epidemiological studies of genetic susceptibility of lung cancer, in which she plays an important role for formulation of hypotheses, study design, performing laboratory assays and data analysis, and has successfully developed and evaluated several genetic risk biomarkers for lung cancer, including mutagen sensitivity, DNA damage-induced G2/M arrest, telomerase activity in tumor tissue and functional genetic polymorphisms. Georgetown University Collaborators |
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