Aim 2: Develop and Test Approaches for Primary Cancer Prevention Through Chemoprevention Research Efforts Mayo Clinic serves as the research base for the multi-center Cancer Prevention Network (CPN), an interdisciplinary consortium funded by one of six National Cancer Institute (NCI) contracts awarded nationally to support Phase I and II clinical trials of novel chemoprevention agents. Paul Limburg, M.D., serves as Principal Investigator for the CPN consortium, which includes more than 112 specialists from community clinics and medical centers located in 27 states and two Canadian provinces. Trials are designed in collaboration with NCI staff. In addition, Mayo investigators as detailed below have organized and conducted chemoprevention trials through the NCCTG, as well as through focused, project-defined collaborations. We highlight recent and ongoing clinical trials, by target organ: Colorectal Cancer Trials
Using the CPN infrastructure, Dr. Limburg (Study Chair), along with Frank Sinicrope, M.D., Thomas Smyrk, M.D., Russell Heigh, M.D., Charles Erlichman, M.D. (Developmental Therapeutics), and other extramural collaborators are investigating the effects of a six-month intervention with atorvastatin, sulindac, RAFTILOSE® Synergy1 (a bifidogenic, prebiotic agent) or placebo with respect to percent change in the number of rectal aberrant crypt foci (ACF) among subjects with a history of colorectal neoplasia. The primary endpoint for this Phase II study is based on magnification chromoendoscopy findings obtained pre- and post-intervention, with secondary endpoints based on tissue-based biomarkers of proliferation (Ki67 expression) and apoptosis (caspase-3 expression). Because this trial includes a placebo arm, the resulting data should further advance current understanding regarding the natural history of rectal ACF. Dr. Sinicrope has received funding (R01 CA113681) to conduct a randomized, placebo controlled trial of aspirin alone, or in combination with calcium carbonate or difluoromethylornithine, among subjects at increased risk for recurrent colorectal neoplasia. Percent change in the number of distal colorectal aberrant crypt foci (ACF) will be measured at 12 months as the primary endpoint. Secondary endpoints will include other ACF characteristics (size/morphology, histopathology, gene expression profiles) and several tissue-based biomarkers (drug targets, mucosal polyamine levels, apoptotic and proliferative indices, downstream effectors of EGFR, and COX-2-dependent apoptotic regulatory genes). He also proposes to evaluate the chemopreventive potential of green tea derivatives against intermediate endpoints of sporadic colorectal carcinogenesis in a randomized, multi-center, Phase II clinical trial. Esophagus Investigations
Barrett's esophagus is a recognized precursor for esophageal adenocarcinoma, which has one of the most rapidly rising incidence rates of all cancers in the United States. In a CPN-coordinated trial, Yvonne Romero, M.D.; Kenneth Wang, M.D.; Navtej Buttar, M.D.; Thomas Smyrk, M.D.; Herbert Wolfsen, M.D.; Virender Sharma, M.D.; and Dr. Limburg; along with other extramural collaborators; are testing the hypothesis that the combination of a proton pump inhibitor plus aspirin is more effective than a proton pump inhibitor alone for modifying cancer risk among Barrett's esophagus patients. The primary endpoint of this multi-center, Phase II trial is absolute change in tissue PGE2 concentration, as determined from Barrett's esophagus mucosal biopsy samples obtained pre- and post-intervention. Additional tissue-based biomarkers (Ki67, caspase-3, and COX-2) will be analyzed as secondary endpoints. Lung Studies
Epidemiologic data support an inverse association between regular nonsteroidal anti-inflammatory drug (NSAID) use and bronchial adenocarcinoma. Laboratory studies have further shown that COX-2 may be an important target in pulmonary carcinogenesis. James Jett, M.D. (Study Chair), Marie-Christine Aubry, M.D., Dr. Limburg and other extramural colleagues are currently conducting a CPN-sponsored, Phase II trial of sulindac versus placebo among subjects at increased lung cancer risk due to long-term cigarette smoking and/or personal history of non-small cell lung cancer. The primary endpoint of this multi-center study is the change in histologic grade of bronchial dysplasia, as determined from mucosal biopsy samples obtained during autofluorescence bronchoscopy exams performed pre- and post-intervention. Secondary outcomes include changes in the number of dysplastic lesions and in tissue expression of COX-2, 15-LOX-1, PPARγ, Ki-67, caspase-3, cyclin D1, and cyclin E. Building from a recently completed Phase I trial at the British Columbia Cancer Agency, Drs. Limburg and Aubry are also collaborating with Stephen Lam, M.D. (Study Chair; British Columbia Cancer Agency), and colleagues to conduct a Phase II trial of myo-inositol for lung cancer chemoprevention among high-risk subjects, which is in the final stages of protocol development through the CPN consortium. Cervical Cancer Prevention
HPV infection has been identified as a major risk factor for cervix cancer and dysplasia. Persistent infection implies failed immune response to the virus, and is associated with a high risk for cervical dysplasia and cancer. Dr. Loprinzi and Bobbie Gostout, M.D., recently completed an R01-funded trial to evaluate the impact of imiquimod, a topical medication used for HPV related genital warts, as an adjunctive treatment for dysplasia. The trial design involved randomizing women with recurrent dysplasia to receive a cervical application of imiquimod with their standard care versus standard care. Outcomes included recurrent dysplasia as well as vaginal and serum cytokine levels and vaginal HPV analysis. Although the trial results did not find statistically significantly improved HPV clearance in the imiquimod treated group, important information from this study was gained regarding immune response and vaginal cytokines. The manuscript is in the final stages of development and is scheduled to be submitted for publication in the near future. Molecular Targets and Biomarker Discovery
Dr. Sinicrope is investigating novel pathways of colorectal carcinogenesis at multiple levels. Using biopsy samples obtained from familial adenoma polyposis patients who participated in a recent chemoprevention trial organized by M.D. Anderson Cancer Center, he and his extramural colleagues showed that suppression of cell proliferation, an increased apoptotic ratio and the ratio of apoptosis to cell proliferation were associated with polyp regression, suggesting potential mechanisms for celecoxib's chemopreventive efficacy in this genetically predisposed subject population. Although environmental factors appear to be important in modulating colorectal cancer risk, the intracellular events associated with most disease-modifying exposure agents remain incompletely defined. Dr. Limburg is currently examining the molecular epidemiology of sporadic colorectal cancer subtypes in a population-based cohort study through an NCI R01 grant. Additional collaborators include Dr. Smyrk, Stephen Thibodeau, Ph.D., and James Cerhan, M.D., Ph.D. (GERA Program). Specifically, associations between cigarette smoking, estrogen exposure, and folate intake are being estimated by distinct colorectal cancer subtypes, including microsatellite instability phenotype, Ki-ras or p53 mutations, and CpG island methylator phenotype. Dr. Buttar's laboratory is characterizing the molecular mechanisms associated with carcinogenesis in Barrett's mucosa to inform more targeted chemopreventive interventions. Chronic esophageal reflux injury has been implicated in the pathogenesis of Barrett's esophagus-associated esophageal adenocarcinoma. Further, contents of the esophageal refluxate activate PGE2 synthesis in Barrett's esophagus. Dr. Buttar is conducting a series of inter-related experiments to address the molecular mechanisms of KLF11-mediated inhibition of the PGE2 pathway in Barrett's epithelium, to address PGE2 dependent and independent cellular mechanisms of the tumor suppressive role of KLF11 in Barrett's epithelium, and to determine the in vivo relevance of KLF11 on the neoplastic transformation in Barrett's mucosa, by using KLF-/- mice with reflux. The Buttar lab is also characterizing the importance of constitutive NF-κB activation in reflux-induced esophageal adenocarcinoma using an established animal model of Barrett's esophagus, which is anticipated to facilitate broader understanding of pro-carcinogenic mechanisms in Barrett's esophagus and advance the development of novel chemopreventive agents. In collaboration with investigators from the Eppley Institute for Research in Cancer and Allied Diseases, Sandhya Pruthi, M.D., and James Ingle, M.D., are exploring the hypothesis that estrogens can become endogenous carcinogens via formation of catechol estrogen quinones, which react with DNA to form specific depurinating estrogen-DNA adducts. In a small initial study, estrogen metabolites, conjugates and depurinating DNA adducts in urine samples from 46 healthy control women, 12 high-risk women and 17 women with breast cancer were analyzed. The estrogen metabolites, conjugates and depurinating DNA adducts were identified and quantified by using ultraperformance liquid chromatography/tandem mass spectrometry. The levels of the ratios of depurinating DNA adducts to their respective estrogen metabolites and conjugates were found to be significantly elevated among high-risk women (p < 0.001) and women with breast cancer (p < 0.001) compared to control subjects, suggesting that depurinating estrogen-DNA adducts represent potential early detection and/or effect biomarkers for future breast cancer prevention studies. New Therapy Development
Joel Reid, Ph.D., and Matthew Ames, Ph.D., of the Developmental Therapeutics Program along with Dr. Limburg recently completed a CPN-coordinated, single-dose, two-period cross over trial to assess the bioequivalence of sulindac in capsule versus tablet formulations. Overall, bioavailability appeared to be higher for the capsule compared to the tablet formulation, based on test-to-reference pharmacokinetic parameter ratios for the parent compound alone. However, additional analyses based on the sulfide and sulfone metabolites of sulindac indicated similar chemopreventive exposures between the capsule and tablet formulations. These data support the use of sulindac capsules, which can be readily prepared with matching placebos, in future blinded chemoprevention trials. Drs. Reid and Limburg are also in the final stages of protocol development for NCI's first-ever Phase 0 chemoprevention trial, which will evaluate five different formulations of SR13668, an orally active AKT pathway inhibitor. This study will be coordinated through the CPN infrastructure and involves collaboration with investigators from the Center for Drug Delivery Research, University of Kansas. Further, Dr. Limburg is partnering with Zigang Dong, M.D., Dr.P.H., and Ann Bode, Ph.D., from the Hormel Institute, University of Minnesota, to develop 6-gingerol as a candidate skin cancer prevention agent. Animal studies are currently ongoing, with anticipation of a Phase I, dose-finding clinical trial to be conducted pending final analyses of the preclinical data.
Traditional Pharmacotherapy
Mayo's nicotine research program continues to expand and investigators have led and participated in a number of pharmacological agent studies. A current line of research is utilizing varenicline in a number of venues, including evaluating efficacy for treating smokers with COPD and a new R01 submission by Richard Hurt, M.D., for varenicline treatment for recovering alcoholic smokers. The NDC's widening experience with this medication has led to research in the use of varenicline for smokeless tobacco users with Jon Ebbert, M.D., performing preliminary studies funded through the Cancer Center by the Fraternal Order of Eagles leading to the submission of an R01. Dr. Ebbert has also performed preliminary studies funded through the Cancer Center by the Fraternal Order of Eagles combining varenicline with bupropion to treat tobacco dependence in smokers, which has also led to a new R01 submission.
Dr. Hurt is a co-investigator on a multicenter grant testing methylphenidate for treating tobacco dependence in smokers with ADHD and he recently was awarded an R21 to test the efficacy of methyplphenidate for treating tobacco dependence in smokers. Amit Sood, M.D., conducted an intramurally-funded pilot study which led to a trial using gabapentin for treating tobacco dependence. Dr. Sood, in collaboration with Dr. Ebbert, has also initiated a pilot trial using varenicline and sibutramine to treat smokers with the aim of testing whether the combination will help smokers to stop smoking without gaining weight.
Nicotine researchers have collaborations with colleagues in the Department of Laboratory Medicine seeking to develop capabilities of assaying biological fluids for tobacco alkaloids. Recently Thomas Moyer, Ph.D., developed, tested, and instituted for research and clinical purposes the ability to measure nicotine, cotinine, trans-3-hydroxycotinine, anabasine, and nornicotine, utilizing HPLC-tandem mass spectrometry methodology. This allows researchers to measure these tobacco alkaloids at a level of precision not previously available at Mayo Clinic. This capability has resulted in better clinical practice, especially in the Mayo Clinic Transplant Program. In order to go onto the heart transplant list, the patient must be abstinent from tobacco for a minimum of six months. If the patient is a tobacco user, treatment in our Residential Treatment Program is mandated by the transplant team. The transplant team utilizes the highly specific tobacco alkaloid assays from Dr. Moyer's laboratory to biochemically confirm the patient's abstinence from tobacco and also to distinguish between tobacco use and nicotine replacement therapy.
Complementary and Alternative Medicine Approaches
Dr. Sood has ongoing research utilizing a range of complementary and alternative medicine approaches. He began this line of research by surveying patients at the Nicotine Dependence Center regarding their previous use of complementary and alternative medicine approaches to treat their tobacco dependence. Not surprisingly, 27 percent reported prior use but 67 percent reported interest in future use of CAM approaches. His first grant investigated the efficacy of St. John's Wort in treating tobacco dependence. He has recently been awarded a grant to test the efficacy of SAMe for treating smokers. Other ongoing projects include using meditation to prevent relapse to smoking and a very novel project using dark chocolate to treat light smokers.
Alcoholic Smokers
The prevalence of smoking in alcoholics is 2 to 3 times that of the general population. Mayo investigators have had ongoing research in this area for a number of years. Searching for effective treatments for alcoholic smokers led them to capitalize on their considerable experiences with varenicline resulting in a new grant "Efficacy of Varenicline for Recovering Alcoholic Smokers." This research will be conducted in collaboration with the University of Minnesota.
Smokeless Tobacco
Smokeless tobacco use is a major health and addiction problem, particularly for adolescent and young adult males. Long-term use increases the risk of developing a number of oral/periodontal diseases or cancer. Continued smokeless tobacco users reported a high level of nicotine dependence. To address this, Dr. Ebbert, Steven Ames, Ph.D., and Lowell Dale, M.D., determined that barriers to quitting included lack of motivation, nicotine withdrawal symptoms, and stress. These findings have encouraged Dr. Ebbert to continue to refine pharmacologic interventions for smokeless tobacco users and to pursue high-dose nicotine replacement therapy and new pharmacotherapies, such as varenicline. He collaborated with Drs. Hurt, Dale and Moyer; and investigated the use of serum tobacco alkaloids as a biomarker of systemic nicotine exposure in smokeless tobacco users. They determined that serum nicotine was superior to cotinine for this purpose.
With funding through the Cancer Center from the Fraternal Order of Eagles, Drs. Ebbert, Dale, Hurt and Ivana Croghan, Ph.D., conducted an open label pilot study treating smokeless tobacco users using the 4 milligram (mg) nicotine lozenge. Biochemically-confirmed 7-day point prevalence tobacco abstinence 12 weeks (end-of-treatment) was 53 percent and 47 percent at six months, which led to the submission and funding of a new grant and continued study. In the new clinical trial, Drs. Ebbert, I. Croghan, and Hurt are investigating the efficacy of the nicotine lozenge for smokeless tobacco users. They are collaborating as well with Herbert Severson, Ph.D., at the Oregon Research Institute in Eugene, Ore.
Dr. Ebbert has also competed successfully for funding from the Fraternal Order of Eagles for an open label trial using varenicline and bupropion for smokeless tobacco users. His ongoing collaborative relationship with Dorothy Hatsukami, Ph.D., at the University of Minnesota has now developed to the point that the University will be a site for the varenicline/bupropion grant submission in June 2008.
In a related pilot project Paul Limburg, M.D., in collaboration with Drs. Hurt and I. Croghan developed and pilot tested a scannable questionnaire to survey patients who come for gastrointestinal endoscopy at Mayo Clinic in Rochester, Minn., to assess their tobacco use history. It is known that cigarette smoking has been associated with increased risk for esophageal squamous cell carcinoma, esophageal adenocarcinoma, and colorectal adenocarcinomas, but observational data regarding the use of smokeless tobacco and gastrointestinal cancer risk have not been rigorously examined. Since smokeless tobacco contains many of the same carcinogens found in cigarettes and since smokeless tobacco users frequently swallow their tobacco juice, this likely would increase the topical gastrointestinal exposure to carcinogens and may increase the risk of malignant transformation at one or more sites within this organ system. Dr. Limburg has surveyed over 3,000 patients and data analysis is in progress. If a relationship is shown, this will open up an avenue of research, not only for interventions for smokeless tobacco users but also to establish the feasibility of collecting cancer risk factor data from a large patient population with the documented presence or absence of gastrointestinal mucosal lesions, develop data collection instruments (in scannable format) that may be applied to observational studies of multiple gastrointestinal cancers, and to construct the foundation for a data resource that will facilitate future large-scale epidemiologic investigations of gastrointestinal cancer risk and protective factors.
Treating tobacco dependence in cancer patients and outcome evaluations of patients treated at the NDC Treatment Program
Very little work has been performed in treating tobacco dependence in patients with cancer, but Mayo investigators continue to try to close the research gap. Yolanda Garces, M.D., in the Department of Radiation Oncology has a number of ongoing projects treating tobacco dependence in Radiation Oncology patients. Along with Dr. Hurt and Gary Croghan, M.D., Ph.D., her research fills a major void in available knowledge. Her research shows that head and neck cancer patients who have been treated in the Nicotine Dependence Center Treatment Program who continue to smoke are much more likely to develop a second primary cancer, and this happens within a very short period of time (i.e., 1 to 3 years). Dr. Garces is continuing this work through an intramurally-funded CR20 grant "Tobacco Use in Radiation Oncology Patients."
Dr. Ames has also continued to help evaluate the NDC's clinical program by performing an analysis of different variables in the Residential Treatment Program and found that there was improvement across a range of psychosocial factors. Finally, Dr. I. Croghan and Sandhya Pruthi, M.D., (Women's Cancer Program) have utilized intramural funding and existing databases to evaluate the potential relationship between smoking and breast cancer or other breast diseases and to evaluate the NDC Treatment Program outcomes to determine if there are differences based on gender. Dr. I. Croghan along with Dr. Hurt and Charles Loprinzi, M.D., published the results of the third North Central Cancer Treatment Group (NCCTG) trial of treatments for smokers in a randomized comparison of a nicotine inhaler and bupropion and reported that the nicotine inhaler significantly increased smoking abstinence beyond the effect of bupropion alone.
Young Adult Smokers and Surgical Patients
Dr. Ames conducted a journaling project for young adult smokers and successfully competed for a Florida Department of Health New Investigator Award through the Florida Biomedical Research Program "Stress Management Intervention for Young Cigarette Smokers." This line of research has now resulted in the 2007 submission of an R21, "Refinement of the Adolescent Minor Stress Inventory." He is also primary investigator of an R21 entitled "Smoking Cessation for Young Adults who Binge Drink." In fact, his collaboration with Chudley Werch, Ph.D. at the University of Florida has led to a line of research in tobacco use interventions for young adults ranging from high school age to college age. Dr. Ames is a co-investigator on Dr. Werch's grant "A Selective Preventive Intervention for High School Seniors," and also has obtained a grant from the Lance Armstrong Foundation, "Brief office intervention to improve the quality of life of prostate cancer patients with biochemical recurrence."
Ethnic and Racial Differences
Drs. G. Croghan, I. Croghan, Hurt, Loprinzi and others have submitted a manuscript titled A Comparison by Ethnicity of a 15 mg/16 Hour Nicotine Patch Alone Versus Nicotine Nasal Spray Alone Versus Both. The purpose of this report was to compare the smoking abstinence in smokers of different ethnic backgrounds (Caucasian versus non-Caucasian) using nicotine patch and/or nicotine nasal spray. This study showed that minorities were less likely to be married (51 percent versus 64 percent, minorities to Caucasians, respectively), more likely not have graduated from high school (15 percent versus 5 percent, respectively), were smoking fewer cigarettes per day at baseline (21 versus 27, respectively), were less likely to have had past quit attempts (79 percent versus 86 percent, respectively), and were more likely to have had a personal history of depression (30 percent versus 20 percent, respectively). A significant difference in smoking abstinence was noted between minorities and Caucasians at the end of treatment (11 percent versus 22.2 percent, respectively) and end of study (4 percent versus 9 percent, respectively).
Surgical Patients
David Warner, M.D., a collaborator from the Department of Anesthesiology, has a developed line of research in tobacco dependence in surgical patients including an international collaboration in a survey of Japanese physicians on perioperative tobacco use interventions. Through a project, "Smoking and Stress in the Perioperative Period," funded by the Minnesota Partnership for Action against Tobacco, Drs. Warner, Ames and Christi Patten, Ph.D., determined that nicotine replacement therapy is not always needed to manage nicotine withdrawal or stress in smokers undergoing surgery. This has led to a line of research in surgical patients who are smokers. Through intramural funding, Drs. Warner, Hurt, and I. Croghan investigated the occurrence of coughing after a smoker stops smoking and found that an increase in coughing after stopping smoking is not common among otherwise healthy patients. Dr. Warner also has ongoing research on the preoperative use of nicotine lozenges to reduce nicotine withdrawal in smokers and the use of nicotine nasal spray to prevent postoperative nausea and vomiting in smokers undergoing surgery. Dr. Warner has a funded R03 grant, "Elective Surgery as a Teachable Moment for Smoking Cessation," and another peer-reviewed grant from ClearWay Minnesota entitled, "Tobacco Helpline in Surgical Patients who are Smokers."
Tobacco Document Research
The Minnesota Tobacco Trial of 1998 resulted in the release of over 50 million pages of previously secret tobacco industry documents and has dramatically changed the field of tobacco control. Over 450 peer-reviewed papers have now been published based on these documents, most of which have been funded by the National Cancer Institute. Dr. Hurt successfully renewed his tobacco document research grant, "Tobacco Industry Documents on ETS - The Next Front," and added Dr. Ebbert as a co-investigator in 2007 along with Monique Muggli. Based on the worldwide nature of the tobacco epidemic and the connection between British American Tobacco and its subsidiary, Souza Cruz, in Brazil, the renewed grant includes a collaboration with Analice Gigliotti, M.D., a colleague in Rio de Janeiro. This research will allow the investigators to identify the scope of the Brazilian tobacco industry's campaign against environmental tobacco smoke (ETS) and define its role in producing genetically-altered tobacco and smuggling. In addition Drs. Hurt and Ebbert and Ms. Muggli reported on the tobacco industry's efforts to eliminate polonium from cigarettes and eventually to suppress the fact that this could not be done in a publication entitled "Waking a sleeping giant: the tobacco industry's response to the polonium-210 issue." This team is leading a collaborative effort with Kelley Lee, D.Phil., also a National Cancer Institute-funded tobacco document researcher of the London School of Hygiene and Tropical Medicine, in an extensive assessment of smuggling of cigarettes into Africa by the industry and what cigarette manufacturers have done to thwart smoke-free workplace policies in China and Spain.
Genetic Epidemiology and Risk Assessment Program
Dr. Ebbert has developed extensive collaborations with investigators in the Genetic Epidemiology and Risk Assessment Program. Along with GERA Program collaborators Ping Yang, M.D., Ph.D.; James Cerhan, M.D., Ph.D.; and Mariza de Andrade, Ph.D.; he is researching various aspects of lung cancer risk reduction after smoking cessation from the Iowa Women's Health Study. Dr. Ebbert also has worked with Dr. Yang on a number of other projects, including alpha1-antitrypsin and lung cancer risks and the glutathione metabolic pathway in lung cancer.
Minnesota Tobacco Control Research and Policy Center
The breadth of expertise in tobacco research, treatment, and education at the University of Minnesota and Mayo Clinic is unique in the world and represents an unparalleled opportunity to create a world class tobacco control multidisciplinary research team that seeks to have high prominence as the leader in the field. Together the institutions are developing the Minnesota Tobacco Control Research and Policy Center, co-led by Drs. Hatsukami and Hurt, to promote collaborative and strategic scientific investigations and to translate these findings into policies, programs, and educational endeavors in order to prevent tobacco related disease and reduce tobacco use in Minnesota, the United States, and globally.
Specifically, this center will:
- Develop unified and common goals among investigators and with community members
- Provide an infrastructure that promotes communication and collaboration
- Increase the number of interdisciplinary research teams and amount of research funding
- Promote training of students and career development of young faculty
- Promote communication of our results to other scientists, tobacco control advocates, health care program directors, and policy makers with the goal of bringing national and international visibility and prominence to our center and the University of Minnesota and Mayo Clinic
- Facilitate the translation of our research so that our findings would affect changes in policies, programs, and be used to educate health care professionals that will positively affect public health
- Create a strong global presence through training and research
The Center will establish linkages throughout relevant dimensions of the University and Mayo communities - from basic biology to international prevention and treatment - but will reach significantly further, for example, to include treatment service providers such as Blue Cross Blue Shield Minnesota and valuable industrial partners engaged in the development of medications and biomedical instrumentation. By developing infrastructure supported by intramural resources, the investigators will efficiently integrate the existing tobacco control efforts which are wide ranging but diffusely located into an overarching framework which in turn will support cohesive approaches to facilitate the acquisition of extramural funding to support ongoing research, training, and clinical practice objectives.
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