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1、Common Pathogenetic Mechanisms of Lung Cancer and COPDPeter Greenwald, MD, DrPHProgram Director: Eva Szabo, MDDivision of Cancer Prevention, NCINational Cancer InstituteU.S. DEPARTMENT OF HEALTH AND HUMAN SERVICESNational Institutes of HealthLung Cancer and Chronic Obstructive Pulmonary Disease (COP
2、D): Two Sides of the Same Coin?Leading causes of morbidity and mortalityDeaths in 2005: 159,415 (lung ca.), 127,100 (COPD)Shared environmental risk factor (tobacco)10-15% of smokers lifetime incidenceCOPD increases lung cancer risk up to 4.5-fold (independent of tobacco exposure)COPD in non-smokers
3、also increases lung ca riskCommonalitiesInflammationlung cancer risk in COPD patients using inhaled steroidsSomatic mutations and histologic changes in exposed fieldMSI in sputum cells from smokers with COPD, but not without COPDPathogenesis of Lung Cancer and COPD-Modified fromBrody JS & Spira A, P
4、roc Am Thorac Soc2006;3:535Stochastic or Genetic COPDCANCER“NORMAL”CIGARETTE SMOKEROSNF-BInflammationGene activation/silencing-Apoptosis+ DNA Damage/?repairGENOME INSTABILITYClonal ExpansionInvasion-angiogenesisMatrix Degradation/?repairIMMUNE RESPONSECOPEObjectivesTo identify fundamental pathogenet
5、ic commonalities between lung cancer and COPD in order to characterize:Genotypic and phenotypic characteristics that identify individual susceptibilityShared biochemical, molecular, and immunologic pathways involved in the origin and progression of both diseasesTranslational initiative focusing on h
6、uman studies, ultimate goal to identify populations and molecular targets for clinical trials for prevention of lung cancer & COPDExamples of ApplicationsClarify co-epidemiology of lung cancer and COPDclinical characteristics and molecular phenotypesshared genetic and epigenetic risk factorsgene-env
7、ironment interactionsattention to early molecular events, timing, subsequent course of each Examples of ApplicationsInvestigate common and disparate mechanisms involved in the pathogenesis of COPD and lung cancerrole of innate and adaptive immunity, redox balance, proteinases, injury repair, stem ce
8、ll proliferation, epigenetic changes, somatic mutations, microenvironment, and epithelial-mesenchymal transitionExamples of ApplicationsIdentify and validate biomarkers, molecular signatures, and imaging measures of risk, presence, severity, and progression of COPD and lung cancer and of responses t
9、o therapySpecific example: COPDGene, a 10,500 person COPD GWAS trial with high resolution CTs opportunity to study natural history of ground glass opacities (AAH, putative precursor to lung ca.) and lung cancer risk across varying degrees of COPDLung Cancer-COPD InitiativeFunding mechanism:R01Length
10、 of Awards:4 yearsAnticipated Award Date:FY2011NCI Amount Set Aside 01 Year:$3M*Total NCI Amount for 4 Years:$12MAnticipated # Awards:6-8Total NCI+NHLBI Amount, 4 Yrs:$24M *NHLBI approved same concept for $3M/yr x 4 yrs, contingent on NCI funding Unique Aspects of InitiativeFull partnership between
11、NCI and NHLBI Double PI governance, one from cancer and one from pulmonary community strongly encouragedHistorically separate research communitiesAnnual meeting of all PIs in Bethesda (set aside funds)Encourage collaboration, specimen/data sharingSecure web-site (set aside funds) for potential colla
12、borative avenues, specimen/methodology sharing, etc.Current Portfolio Analysis: Lung Cancer and COPD2008 $3.8M NCIOne R01: 1-antitrypsin genotypes and lung cancer riskOne U01: phase IIb clinical trial, green tea polyphenols in former smokers with COPD4 studies on lung cancer risk and genetic/epigene
13、tic abnormalities (do not address COPD specifically)Other institutesNHLBI: One R01 on neutrophil elastase in COPD and lung cancerNIA: One R01 on COPD as a co-morbid condition in older cancer pts.Rationale for RFAArea of high importance not well represented in RPG pool, “falls between the cracks”Stim
14、ulate new collaborative research between cancer and COPD communities (historical organizational barriers)Leverage scientific knowledge and clinical expertise from 2 distinct research communitiesReview panel with specialized expertiseIntegration with other research infrastructures (e.g., EDRN, SPOREs
15、, NHLBI LTRC and SPIROMICS programs) NHLBI-NCI Working GroupPunturieri A et al., Lung Cancer and COPD: Needs and Opportunities for Integrated Research, JNCI, in pressWorkshop June 26/27, 2007 Bethesda, MDChairs Stephen D. Shapiro, MD and Steven M. Dubinett, MDNHLBI (Division of Lung Diseases) Antonello Punturieri, MD, PhDThomas L. Croxton, MD, PhDGail Weinman, MDNCI (Division of Cancer Prevention)Eva Szabo, MD
