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    Wiseman opac2013 Wiseman opac2013 Presentation Transcript

    • Martin WisemanMedical and Scientific AdviserWCRF InternationalLondonUKVisiting Professor of Human NutritionUniversity of SouthamptonUKContinuous Update Project -Systematic Review of Mechanistic Evidence
    • Journal citations - WCRF/AICR Reports0501001502002503003504004505001997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011NumberofcitationsDoll & Peto 19811997 EXPERT REPORT2007 EXPERT REPORT
    • BreastGlobal variation in cancer incidenceColorectum
    • Migration data Trends in incidence(Japan)CancerIncidencePer 100,000, world population standard
    • Systematic reviews• Expert international Task Force for method• Nine centres - USA, UK, NL, Italy• SLR centre coordinator• Test of reproducibility• Standardised search, analysis and display• Epidemiology and mechanisms• Quality assessment• Peer review - protocol, report• Defined expertise required– Nutrition, epidemiology, systematic review, cancer biology, statistics
    • Inferring causality• Strength• Consistency• Specificity• Timing• Dose Response• Plausibility• Coherence• Experiment• AnalogyBradford Hill
    • GRADING CRITERIAPredefined requirements for:–Number and types of studies–Quality of exposure and outcome assessment–Heterogeneity within and between study types–Exclusion of chance, bias or confounding–Biological gradient–Evidence of mechanisms–Size of effect
    • Basis forrecommendations• Convincing• Probable• Limited Evidence – Suggestive• Limited Evidence – No Conclusion• Substantial Effect on Risk UnlikelyGRADING THE EVIDENCE
    • OBITUARYWylieValeandan elusivestresshormonep.542HISTORYOFSCIENCEDescartes’lost letter trackedusingGooglep.540EARTHSYSTEMSPast climatesgivevaluablecluestofuturewarmingp.537AVIANINFLUENZAShift expertisetotrack mutationswherethey emergep.534Raisestandardsforpreclinical cancer researchC. Glenn Begley and LeeM. Ellisproposehow methods, publicationsandincentivesmust changeif patientsaretobenefit.Manylandmark findings in preclinical oncology researchare not reproducible, inpart because of inadequate cell linesand animal models.S.GSCHMEISSNER/SPLCOMMENT29 MARCH 2012 | VOL 483 | NATURE | 531
    • OBITUARYWylieValeandan elusivestresshormonep.542HISTORYOFSCIENCEDescartes’lost letter trackedusingGooglep.540EARTHSYSTEMSPast climatesgivevaluablecluestofuturewarmingp.537AVIANINFLUENZAShift expertisetotrack mutationswherethey emergep.534Raisestandardsforpreclinical cancer researchC. Glenn Begley and LeeM. Ellisproposehow methods, publicationsandincentivesmust changeif patientsaretobenefit.Efforts over the past decade tocharacterizethegeneticalterationsinhumancancershaveledtoabetterunderstandingof molecular driversof thiscomplexset of diseases.Althoughweinthecancer fieldhopedthat thiswouldleadtomoreeffectivedrugs,historically,our abilitytotranslatecancer researchtoclinical suc-cesshasbeenremarkablylow1.Sadly,clinicaltrialsinoncologyhavethehighest failureratecomparedwithother therapeuticareas.Giventhehighunmet needinoncology,itisunderstandablethat barrierstoclinicaldevelopment maybelower thanfor otherdiseaseareas,andalarger number of drugswithsuboptimal preclinical validationwillenter oncologytrials.However,thislowsuc-cessrateisnot sustainableor acceptable,andinvestigatorsmust reassesstheir approachtotranslatingdiscoveryresearchintogreaterclinical successandimpact.Manyfactorsareresponsiblefor thehighfailurerate, notwithstandingtheinher-entlydifficult natureof thisdisease. Cer-tainly, thelimitationsof preclinical toolssuch asinadequatecancer-cell-lineandmousemodels2makeit difficult for evenManylandmark findings in preclinical oncology researchare not reproducible, inpart because of inadequate cell linesand animal models.S.GSCHMEISSNER/SPL2 9 M A RC H 2 0 12 | V O L 4 8 3 | N A T U R E | 5 3 1COMMENT© 2012MacmillanPublishersLimited.All rightsreserved29 MARCH 2012 | VOL 483 | NATURE | 531• Reproducibility• Relevance of model• Relevance of exposure• Relevance of dose• Route of administration• Publication bias
    • Mechanisms Protocol DevelopmentGroupExternal Experts Stephen Hursting (chair) Andrew Dannenberg Johanna Lampe Henry Thompson Steven Clinton Nikki Ford - associate memberWCRF Team Martin Wiseman Susan Higginbotham Rachel Thompson Rachel Marklew Kate Allen Deirdre McGinley-Gieser
    • HALLMARKS OF CANCERClassic Hallmarks• Sustaining proliferativesignaling• Evading growth suppressors• Resisting cell death• Enabling replicativeimmortality• Inducing angiogenesis• Activating invasion andmetastasisEmerging hallmarks• Deregulating cellularenergetics• Avoiding immunedestructionUnderpinningcharacteristics• Genome instability• InflammationHanahan and Weinberg 2011
    • MechanismsReviews to be systematic and peerreviewedReviews conducted by exposureFeasibility test of final draft protocol byexternal group, including peer reviewExternal review team should haveexpertise in informatics, stats, cancerbiology, cancer site, nutritionMolecular, cellular, physiological…
    • Thank you!