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University of Colorado Cancer Center
Project 1 SPORE Project 1 originated with discoveries about genetic changes of human chromosome 3 in lung cancer. One characteristic of most cancer cells is that they are genetically unstable. Since cancer cells usually harbor a variety of gene mutations, it is critical to identify those that are directly responsible for tumor development and/or progression. The identification of frequent recurring abnormalities, experimental suppression of tumor formation when the normal gene function is replaced, or the conversion of non-tumorigenic cells to those that form tumors constitutes the mainstay of scientific approaches to identify the most important genetic changes. Through previous SPORE support, we identified certain chromosome 3 genes that were very frequently altered in lung cancer cell lines. Two of these genes, - WNT7A and catenin, are components of a pathway whose function is activated in colorectal cancer. In contrast, however, we were able to demonstrate in lung cancer cells that activation of this pathway leads to differentiation as part of a mechanism that establishes and maintains cell-cell adhesion through regulation of E-cadherin. We also demonstrated that the survival of lung cancer patients whose tumors had lost E-cadherin was much worse than those cases where the E-cadherin protein expression had been maintained. We also identified the m molecule responsible for E-cadherin loss in lung cancer and demonstrated that pharmacologic blockade of this molecule (using a class of agents called HDAC inhibitors) led to the reestablishment of E-cadherin expression in some tumors. We also found that HDAC inhibitors induced tumor cell death (apoptosis) and that HDAC inhibitors could be combined with other biologic agents in an additive or synergistic manner. One of these agents is Iressa (gefitinib) the epidermal growth factor receptor inhibitor. In collaborative studies with Dr. Samir Witta of our Institution, we have shown that HDAC inhibitors make lung cancer cell lines more sensitive to gefitinib. In another collaboration with Dr. Steve Dubinett (UCLA Lung Cancer SPORE), we found that prostaglandin E2 also blocks E-cadherin expression and that treatment of cells with a cyclooxygenase-2 (COX-2) inhibitor, such as Celebrex, can also restore some E-cadherin function. We feel the data are now sufficiently compelling to explore the role of HDAC inhibitors, alone and in combination, in lung cancer patients. Efforts are now ongoing to begin these trials. The third gene which we identified and found to be either deleted or not expressed in a majority of lung cancers was (semaphorin) SEMA3F, a member of a family of secreted molecules originally identified by neurologists studying the growth of nerve cells. However, this class of semaphorins is now known to antagonize the actions of vascular endothelial growth factor (VEGF), one of the most important molecules that induces new blood vessels in tumors (angiogenesis). We previously demonstrated using patient samples that loss of SEMA3F staining was associated with advanced stage lung cancer and was an early event in pre-malignant lesions. In cell culture experiments, we found that SEMA3F has a repulsing activity on breast cancers and inhibited their attachment, spreading and migration - features known to be important in metastasis. Most recently, we have shown that replacing the SEMA3F gene in a subset of lung cancer cell lines blocks their ability to form tumors in animals. For example, when lung cancer cells with the replaced SEMA3F gene were injected into rats, all animals survived to 100 days. In contrast, all animals injected with the control lung cancer cells (lacking SEMA3F expression) died of rapidly growing tumor by 100 days. In a manuscript now under review for publication, we have identified the regulatory region of the SEMA3F gene that controls its expression. By doing so, we should be able to identify the molecule(s) responsible for extinguishing SEMA3F expression in tumors. Interestingly, SEMA3F expression can also be reactivated by HDAC inhibitors. In addition, we believe that the combination of upregulating SEMA3F and inhibiting VEGF (using existing clinically approved antibodies) will have an additive or synergistic therapeutic efficacy in lung cancer patients. In summary, we have identified different genes from chromosome 3p that play an important role in the development / progression of lung cancer. We have identified pharmacologic approaches to upregulate these genes and have provided strong rationale for the use of HDAC inhibitors, alone and in combination with other agents, in the treatment of lung cancer. Project 2 A fundamental property of cancer is the dysregulation of growth signals leading to promotion of cell division and inhibition of apoptosis. Major growth signaling pathways in small cell lung cancer involve neuroendocrine peptides and the G-protein coupled receptors. Major growth factor signaling pathways in non-small cell lung cancers involve the erb-ß family of growth factors and receptors including the epidermal growth factor and its receptors. The goals of Project 2 are to develop an improved understanding of the growth signal pathways and their dysregulation in lung cancer and to translate this knowledge to the clinic by developing novel growth factor inhibitors and understanding how these inhibitors work. Project 2 investigators are studying a series of bradykinin antagonists dimers that affect neuropeptide signaling in small cell and non-small cell lung cancers. The lead compound termed CU201 (or B201) is completing animal toxicology and is scheduled to enter human clinical trials in 2006. Gefitinib and erlotinib are small molecule receptor tyrosine kinase inhibitors of the EGFR that are approved for use in human lung cancer patients. Determining which lung cancer patients will benefit and determining ways to overcome primary resistance to these agents are being studied in this project. The potential role of these agents for chemoprevention is also under investigation.
Project 3 Prostaglandins are lipid mediators which affect growth and differentiation of many types of cells. Studies from many laboratories including our own have shown that a large fraction of lugn tumors produce very high levels of prostaglandins. While the role of these molecules in the development of lung cancer is not well understood, we have shown that increased levels of the prostaglandin prostacyclin are protective against the development of lung cancer in animal models. In addition, a pharmacological analog of prostacyclin, iloprost, is protective against the development of lung cancer in mice. This has led to the initiation of a clinical trial examining the effects of iloprost in patients at risk for lung cancer. The role of this project is to extend these findings to human lung cancer and to define the mechanisms whereby prostacyclin may inhibit lung tumorigenesis. This project is focused on the enzyme responsible for production of prostacyclin, prostacyclin synthase (PGIS). We are examining the expression of this enzyme, and other enzymes in the prostaglandin pathway in samples of human lung cancer. The presence of these enzymes will be correlated with clinical outcomes of the patients. To examine the mechanisms for these protective effects, our project will use mouse models which the cell surface receptor for prostacyclin is deleted. We are also examining the mechanism for the protective effect of prostacyclin in lung cancer cells to define changes in molecular pathways controlling growth and metastasis of these cells. Finally, we are examining the effects of combinations of drugs which impact the prostaglandin pathway. By preventing the production of prostaglandin E2, which promotes lung tumorigenesis, and simultaneously adding prostacyclin, we hope to achieve synergistic effects to prevent lung cancer growth, which could rapidly be translated to the clinic.
Project 4 One of nine smokers develops lung cancer. We seek to improve our ability to assess lung cancer risk beyond taking a smoking history so that early detection and chemoprevention efforts may be more appropriately focused. The overall objective of this project is to identify biomarkers of neoplastic change in the respiratory epithelium that hold clinical promise for assessment of risk and response to chemopreventive intervention. This objective is based on the hypothesis that a field effect of widespread genetic and epigenetic alterations in the respiratory epithelium precedes lung cancer development. Intermediate endpoint biomarkers may be useful as risk markers or intermediate indicators of efficacy of chemoprevention agents. The biomarkers to be assessed in this project range from bronchial epithelial histology and sputum cytology to molecular correlates of respiratory neoplastic change. All 4 Colorado SPORE projects and a Johns Hopkins SPORE project are collaborating in the discovery of biomarkers that will be developed in this project. The majority of biomarker assays will be carried out by Project 4. There are two goals for this project:
During the past nine years, the University of Colorado SPORE in Lung Cancer has developed a team of basic scientists, pathologists, pulmonologists, medical oncologists,biostatisticians and population scientists who share goals of discovering new knowledge regarding the biology of lung preneoplasia and cancer and translating that knowledge to improved prevention, diagnosis and treatment. At the same time, we have established a High Risk Cohort of over 3000 high-risk individuals from whom we have baseline and follow-up sputum, serum and urine. We have recently added an additional 1500 individuals through collaboration with the Mayo Clinic; these have contributed sputum and serum and have received yearly chest CT for three years. A final group of over 570 patients (overlapping partially with the High Risk Cohort) in Colorado have undergone white light and fluorescence bronchoscopy, either for suspected lung cancer, for sputum cytologic dysplasia, for chemoprevention trials, or as paid research controls; this is the Bronchoscopy Cohort. We now have adequate numbers of incident lung cancers in the High Risk Cohort to carry out cross sectional, longitudinal and nested case control studies for biomarkers in sputum, serum and urine; we have adequate tissue resources for cross sectional case-control studies for markers in bronchoscopic specimens now and will have a mature Bronchoscopy Cohort for longitudinal cohort and nested case control studies within another 2-3 years. We are currently evaluating Iloprost, a long acting prostacyclin analog, in a Phase II chemoprevention trial with bronchial histology as the primary endpoint. This trial is now being extended to the institutions participating in the Lung Cancer Biomarkers Chemoprevention Consortium.
The combination of this team of investigators, tissue and informatics resources provides us with an unprecedented opportunity for the discovery, development, and biological validation of biomarkers of risk for lung cancer and for the assessment of intermediate endpoint markers for use in future and current chemoprevention trials.
Core 1 During the 10 years the Colorado SPORE Tissue Bank Core Laboratory (TBC) has been in existence, two trends have increased the need for optimally processed and preserved specimens from lung cancer patients and subjects at risk for lung cancer. One is the increasing availability of treatment modalities that target specific molecular pathways, such as the ErbB pathway. The second is the shift in focus from clinically symptomatic and usually late stage lung cancers to asymptomatic and early stage or preinvasive lesions in high risk populations. Because of these trends, it has been increasingly important to assess the status of targeted pathways selected for treatment, to monitor the effects of new treatments on biology and prognosis and to define the detailed morphology and expected biological behavior of early lesions. For this work there is no more important tool than tumor or preneoplastic tissue itself. Observations in tumor tissue such as the identification of biomarkers may be extrapolated to more accessible fluid specimens such as blood, sputum, bronchoalveolar lavage fluid, urine and surrogate tissue. National panels charged with assessing the state of the science in lung cancer research have consistently identified lack of adequately preserved and studied tissue samples with clinical correlates as a continuing obstacle to the application and validation of promising molecular and imaging technology to the problem of lung cancer. Specific aims of the TBC then are to:
To accomplish these aims the TBC has established innovative methods for the collection of samples for national and local trials and has become a central repository for the Southwest Oncology Group, the American College of Radiology Imaging Network (ACRIN), of specimen preparation and preservation methods that are required for application of new technologies to tissue analysis. These include preparation of high quality RNA and DNA for microarray analyses, creation of a tissue microarray facility, and tissue culture methods to provide purified cell preparations for molecular and cyogentic analyses. Most importantly, the maturation of the TBC has created a sufficiently large and longstanding resource that it is now possible to create case control scenarios that are sufficient statistical power to support clinical hypothesis testing. Core 2 The primary goal of the SPORE Clinical Trials Core is to provide researchers the necessary tools to successfully conduct pivotal clinical trials in prevention, early detection and screening of lung cancer. Investigators who develop a promising drug or test that warrants evaluation in human subjects seek our assistance. The Core offers a wide range of services including: protocol development, regulatory processing, trial marketing and recruitment, computerized data capturing, tissue collection, safety monitoring, quarterly chart audits, data analysis and manuscript preparation. The Core team is comprised of a medical director and 5 experienced clinical research associates. The teams meets routinely with the principal investigators to review trial status. Over the past 12 years the Core has conducted 25 clinical trials ranging from spiral CT for the detection of small lung cancers, evaluation of biological markers in sputum and lung tissue that may predict lung cancer early, testing a novel bronchoscope that may enhance our ability to visualize premalignant lesions in the airways and evaluating drugs to prevent the development of lung cancer. Core 3 The Lung Cancer Spore Biostatistics and Informatics Core provides statistical support for study design, data collection, and analysis. The members of the Core assist in writing protocols, designing data collection and quality control strategies, collecting and storing data, analyzing the results (including graphical presentation), and contributing to publications and the planning and designing of new studies. Examples of current projects include studies to determine if expression of various biomarkers is related to the risk of lung cancer, studies to determine how to best interpret the characteristics of biopsies from a bronchoscopy to determine if an individual is at risk for developing lung cancer, and studies to develop and evaluate drugs or compounds for preventing or treating lung cancer. Members of the informatics group are also working on databases for storage and retrieval of data for studies that are conducted as part of the lung SPORE. Members of the bioinformatics group provide expertise in analysis and interpretation of genetic expression data, and how that might relate to lung cancer risk. Core 4 The overall objective of this SPORE Laboratory Animal Core is to facilitate preclinical research in human lung cancer through the use of subcutaneous and orthotopic cancer cell and tissue transplants (xenografts) in in vivo pharmacotherapeutic rodent models . In addition, this core will provide breeding and procurement of conventional, wild type, transgenic and gene-null (knockout), genetically altered mice for the study of gene function, cell signaling and novel drug development in cancer cell development and suppression. This shared resource will provide purchase, production breeding of and maintenance of specific pathogen-free, barrier-sustained, conventional, transgenic, knockout and athymic nude mice for SPORE investigators in research projects in this program. This CORE will also provide gross and histopathology services, assist in cancer cell and tissue inoculations and transfers, tumor measurements, harvests and animal model preparations for all program investigators using animal models. Animal studies supported by this CORE are focused on the primary SPORE Program objective which is to decrease incidence and mortality from lung cancer by the discovery of cellular and molecular events involved in the progression of lung cancer and the translation of these discoveries into clinical applications.
Core 5 The goal of the administrative core of the University of Colorado Lung Cancer SPORE is to provide outstanding administrative and fiscal support for the entire program effort and to provide the scientific leadership for the program. The administrative core will oversee all administrative and scientific activities of the SPORE program, review and regulate financial expenditures, develop and prepare reports. The Administrative core consists of the two SPORE principal investigators, Drs. Bunn and Miller; the SPORE executive director. Rae Ann Paden, a 40% grants manager/administrative assistant and 10% financial manager. This core will also develop and circulate research conference schedules, coordinate scientific review, schedule the monthly scientific meetings and aid project investigators in the preparation and publication of manuscripts as well as maintain a record of all publications emanating from this grant. It will oversee the planning and evaluation efforts including the scheduling of visits by the external advisors, the planning and coordinating of the yearly internal retreats and yearly NCI SPORE meetings, the scheduling of meetings and scientists, Executive Committee, Developmental Research Committee and Career Development Committee. The Administrative Core works with the SPORE investigators and NCI program staff to insure compliance with all federal regulations and reporting requirements. It will coordinate activities with the Cancer Center and with other SPORES to ensure that there is no redundancy and to ensure joint projects are conducted in the most economical way. The Administrative Core will assist in community outreach efforts particularly with respect to public relations and community activities through the established Cancer Center mechanisms. The core provides support for the development and career development programs as well as visiting scientist program. The Administrative core oversees the functioning of the other 4 core resources.
Supplemental Funding Lung cancer is the number one cause of cancer death in men and women in the United States and worldwide. While large-scale screening trials have recently been initiated, there are no established screening tests for the early detection of lung cancer, and less than 25% of patients present with surgically curable disease (stages I and II). The cumulative five-year survival rate for lung cancer is approximately 15%, a rate which has shown limited improvement over the last several decades. The majority of lung cancers are now diagnosed in former smokers, emphasizing the need for effective chemoprevention in this large, at-risk population. Improved success in decreasing lung cancer rates will rely not only on smoking prevention and cessation, but also on effective chemopreventive strategies. Inflammatory modulators, particularly the prostaglandins, are proving to be critical in many carcinogenesis models. Large epidemiologic studies have proven an association between regular aspirin use and decreased rates of certain cancers. Manipulation of the arachidonic acid pathway has already proven to prevent specific cancers. We believe that prostaglandins play a key role in lung carcinogenesis and our work to date has shown that manipulation of prostacyclin production chemoprevents lung cancer in pre-clinical models. Prostacyclin is a naturally occurring eicosanoid that possesses anti-inflammatory and anti-metastatic properties, as well as a suppressive role in tumor growth. Animals with high lung levels of prostacyclin, as well as animals receiving oral supplementation with Iloprost (a long-acting oral PGI2 analogue) are protected from developing tobacco smoke and chemical carcinogen induced lung cancer. These positive results have directly led to a National Cancer Institute sponsored Phase II human chemoprevention trial evaluating oral Iloprost in current and former smokers. Our trial consists of Iloprost or placebo administered to patients at high risk for lung cancer (based on abnormal cells in the sputum and certain levels of tobacco exposure) in a double blind, randomized prospective trial of six months duration. Eligible patients are randomly assigned to active treatment or placebo treatment and have bronchoscopy performed to document areas of damage in the airway and the potential response of these areas to Iloprost. We are also examining the lung tissue for other markers that may indicate cancer risk. The Iloprost trial continues to actively recruit participants as part of the Lung Cancer Biomarker and Chemoprevention Consortium and to date has enrolled 50 subjects. *This project is supported through supplemental funds granted under this SPORE award and through funds granted under the LCBCC program. The following institutions collaborate on this project: Johns Hopkins University, University of Texas Southwestern, University of Pittsburgh Cancer Institute, Dana Farber Cancer Institute, Mayo Clinic, Dallas Veterans Affairs Medical Center, University of California Los Angeles, and Vanderbilt University Medical Center. Pilot Projct #1. Biomarkers for the Mutator Phenotype in Lung Cancer Our main hypothesis is that cancer cells have a mutator phenotype that is the result of alterations in "error-prone" DNA repair as catalyzed by TLS (trans-lesion synthesis) family of DNA polymerases. Except for a recent study (1), very little has been done with the TLS polymerases in lung cancer cells. We propose that altered regulation of TLS polymerases will result in a mutator phenotype and is indicative of a poor prognosis. Thus, TLS polymerases may represent important biomarkers in both diagnosis and prognosis as they would allow identification of cancer cells with a "mutator" phenotype. We focused on DNA polymerases i (iota), k (kappa), z (zeta-Rev3/Rev7) and Rev1 as they are well-studied and have been shown to be important for BPDE-induced mutagenesis, which is important in diseases that result from tobacco use such as lung cancer. Pol i mutations in the gene confer lung cancer susceptibility on mice and the protein is overexpressed in both SCLC and NSCLC cell lines (1). We also analyzed human Cdc7 levels as our recent studies in yeast that show that the conserved Cdc7-Dbf4 protein kinase regulates TLS and induced mutagenesis by Rev3-Rev7 (Pol z ) (2). Pilot Project #2. Proteomic Profile of NSCLC Cell Lines Sensitive and Resistant to Gefitinib (ZD 1839, Iressa ) The Epidermal Growth Factor Receptor (EGFR) signaling pathway represents an important target for lung cancer therapeutics. Clinical studies with several EGFR inhibitors have shown these agents to be well tolerated and associated with tumor responses and symptom improvement in patients with lung cancer. Gefitinib (Iressa), a low molecular weight EGFR tyrosine kinase, is one such agent that has shown to be effective in advanced NSCLC. In phase II clinical studies the overall response rate has been low (10-18%), however a further 40-50% of patients derive benefit in terms of stable disease and symptom improvement. Although mutations in the EGFR have been identified as potential marker for patients with dramatic responses, at present there is no effective method to identify in advance which patients will derive benefit from gefitinib treatment. The specific aim of this pilot project is to compare the protein expression profiles of non small cell lung cancer (NSCLC) cell lines that are known to be sensitive or resistant to treatment with gefitinib (Iressa) in an effort to improve understanding of the biological basis of sensitivity and resistance to this agent. Cell lines known to have mutations in the EGFR will be included in the analysis. Such a comparative proteomic approach has potential to result in the identification of predictive markers for therapy with gefitinib. For a given cell line, a comparison is made before and after treatment with gefitinib. Both qualitative (the proteins are identified) and quantitative (the relative amount of a given protein is determined before and after treatment with gefitinib ) proteomic profiles are simultaneously determined using Difference Gel Electrophoresis (DIGE) followed by Mass Spectrometry (MS). Pilot Project #3. "Role of the JNK MAPKs in Lung Tumorigenesis" Research completed by a large number of laboratories have identified selected dominant-acting oncogenes which undergo mutation in the setting of human lung cancer. Among these, mutation of the K-Ras and epidermal growth factor receptor (EGFR) genes have been established in non-small cell lung cancer. In fact, K-Ras represents the most commonly mutated dominant human oncogene in human cancer. Within mammalian cells, K-Ras, a member of the low molecular weight G protein superfamily, functions as a molecular switch to activate numerous signal pathways that mediate the actions of extracellular cues that alter cell properties. Identifying the major signal pathways that signal the acquisition of cancer cell properties by K-Ras oncogenes may potentially unveil novel targets for therapeutic intervention in cancer cells that express this oncogene. The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) superfamily and represent one of many signal pathways activated by K-Ras within cells. Importantly, the JNKs have been invoked as a pro-tumorigenic as well as anti-tumorigenic signal pathway in the setting of cancer. We have used mice in which the genes encoding JNK proteins have been disrupted to test the role of the JNKs in lung tumorigenesis. Our studies reveal that mice lacking JNK1 or JNK2 form approximately twice as many lung tumors as normal mice following injection of the carcinogen, urethane. Moreover, a panel of human non-small cell lung cancer cell lines reveals reduced JNK activity in lung cancer cells relative to normal epithelial cell lines, providing support for an overall negative role of the JNK pathway in lung tumor formation. When active JNK molecules are expressed in human lung cancer cell lines, markedly reduced transformed growth results. Thus, our studies indicate that the JNK pathway is a K-Ras-regulated signal pathway that functions as an inhibitor of cellular transformation. We hypothesize that still undefined mechanisms exist for blunting JNK activity in human lung cancer cells to permit more aggressive tumorigenesis and that restoration of JNK activity in lung cancer cells will significantly reduce lung cancer growth. Pilot Project #4. Epigenetic Modification of the Human Prostacyclin Synthase Promoter in Lung Tumors Eicosanoid pathway metabolites are relatively small, naturally occurring molecules with complex lipid structures. As a group, these compounds are produced by cells in low amounts but have high biological activity. One major class of the eicosanoids is the prostaglandins, including PGI2 and PGE2. Chemically, these two prostaglandins are similar though PGI2 seems to play a preventive role in disease while PGE2 seems to play an inducing role. It is thought that not only the absolute concentration of these two antagonistic molecules is important but also their levels relative to each other. Due to their high biological activity, prostaglandins have been implicated in many diseases such as inflammation, arteriosclerosis, and cancer. Specifically, in human lung cancer, the key enzyme responsible for the production of PGI2, prostacyclin synthase, is significantly decreased by an unknown mechanism(s). In addition, mouse studies have shown that high expression of prostacyclin synthase has a protective effect in lung cancer models. These results lead to the rapid approval of Iloprost, a PGI2 analog, in a chemoprevention clinical trial for individuals at high risk for lung cancer. We are investigating three different potential mechanisms that are known to decrease gene expression in other systems. Decreased prostacyclin synthase expression by one of these mechanisms may cause the imbalance in the PGI2 and PGE2 levels. In cancer, loss of genes in tumor cells (due to lower DNA repair activities) is thought to be a relatively common mechanism for altering gene expression. Loss of the prostacyclin synthase gene (and/or additional portions of its chromosome) has been tested by the microscope-based fluorescence in situ hybridization method in a limited number of human lung cancer tissue samples. So far, the loss of the prostacyclin synthase gene has not been observed. Gene expression can also be altered by very small changes in the DNA sequence. One common mechanism for gene "silencing" is aberrant DNA methylation of the promoter region. We have extensively characterized six human lung cancer cell lines and have observed high levels of DNA methylation in lines, which have no prostacyclin synthase gene expression. DNA sequence changes in an important regulatory element of the prostacyclin synthase promoter could also decrease gene expression. We have demonstrated that the number of short tandem DNA sequence repeats within the prostacyclin synthase promoter can affect its transcriptional activity. In addition, various single nucleotide polymorphisms can also alter the promoter's activity. The future direction of our work is to use our methods to determine the importance of these changes in human lung tissue biopsies at the cellular level. These studies could identify a specific molecular mechanism for decreasing prostacyclin synthase in human lung cancer giving further impetus to develop new prostacyclin analogs for therapeutic intervention. Career Development Award #1 Lung cancer is the number one cause of cancer death in men and women in the United States and worldwide. Improved success in effectively decreasing lung cancer rates will rely not only on smoking prevention and cessation, but also on identifying the highest risk populations and creating effective chemopreventive strategies. Inflammatory modulators, particularly the prostaglandin prostacyclin, are proving to be critical in the development of lung cancer. Manipulation of the arachidonic acid pathway has already proven to prevent specific cancers. We believe that prostaglandins play a key role in lung carcinogenesis and our work to date has shown that manipulation of prostacyclin production chemoprevents lung cancer in pre-clinical models. Prostacyclin is a naturally occurring eicosanoid that possesses anti-inflammatory and anti-metastatic properties, as well as a suppressive role in tumor growth. Currently the National Cancer Institute is sponsoring a Phase II human chemoprevention trial evaluating oral Iloprost in current and former smokers. Our trial consists of Iloprost or placebo administered to patients at high risk for lung cancer (based on abnormal cells in the sputum and certain levels of tobacco exposure) in a double blind, randomized prospective trial of six months duration. The Iloprost trial continues to actively recruit participants as part of the Lung Cancer Biomarker and Chemoprevention Consortium and to date has enrolled 50 subjects. As part of this trial we are collecting blood samples from subjects at the time of enrollment and after 6 months of treatment. White blood cells are isolated from these samples and gene expression analysis is conducted. The goal of analyzing these samples is to determine a 'gene expression signature' for subjects on the trial and to determine, once the study is unblinded, if we can predict ahead of time who will respond to Iloprost. Additionally, we will also be able to determine the effects of chronic Iloprost use on gene expression and this may provide insight into the mechanism of chemoprevention. Ultimately, we envision directing chemoprevention based on easily obtained biological samples like a sample of blood. Career Development Award #2 Treatments for lung cancer have not significantly improved survival, leading to a critical need for new approaches. Peroxisome proliferator-activated receptors (PPAR) are a family of nuclear receptors that function as ligand-dependent transcription factors. Three isoforms have been described, PPARa, g, and d, all of which bind to specific DNA sequences as heterodimers with the retinoic acid X-receptors. Pharmacological agents regulating PPARg have already been developed by the pharmaceutical industry, and are being used as anti-diabetic agents. However, our basic understanding of the physiologic roles of distinct PPAR isoforms in the development of lung cancer is limited. Previous data by our laboratory and others indicate that activation of PPARginhibits transformed growth of lung cancer cells. The focus of this project is to examine the role of PPARgin samples from human lung cancer, and to define the mechanisms whereby activation of PPARgaffects lung tumorigenesis. Studies are examining the expression of PPARgin human lung tumors and correlating expression with clinical parameters. Effects of PPARgon growth and invasiveness of human lung cancer cells is being examined, using molecular and pharmacological approaches. List of Investigators Paul A. Bunn, Jr., MD Anna Barón, PhD Tim E. Byers, MD, MPH Daniel C. Chan, PhD Harry Drabkin, MD Wilbur A. Franklin, MD Robert Gemmill, PhD Mark Geraci, MD Lynn Heasley, PhD Fred R. Hirsch, MD, PhD Stephen Hunsucker, PhD James R. Jett, MD Robert Keith, MD Karen Kelly, MD Timothy C. Kennedy, MD John Kittelson, PhD Al Malkinson, PhD York E. Miller, MD Raphael Nemenoff, PhD Robert S. Stearman, PhD James Stevens, DVM, PhD Marileila Varella-Garcia, PhD Robert Winn, MD Rex C. Yung, M.D. |
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