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Unprecedented opportunities exist for the expanded use of foods andcomponents to achieve genetic potential, increase productivity andreduce the risk of disease

DEFINITIONClinical Endpoint - A characteristic or variablethat reflects how a patient feels, functions orsurvives.Surrogate Endpoint - a biomarker intended tosubstitute for a clinical endpoint. A surrogateendpoint is expected to predict clinical benefit(or harm, or lack of benefit or harm) based onepidemiologic, therapeutic, pathophysiologic orother scientific evidence.Source: Biomarkers Definition Working Group -1998

Surrogate markerIs a response variable for which a test of thenull hypothesis on no relationship to thetreatment groups under comparison is also avalid test of the corresponding nullhypothesis based on the true endpoint.Prentice, Stat. Med., 1989i.e. A laboratory or physical sign that is used instudies as a substitute for a clinically meaningfulendpoint such as pain or death.

Biomarker (Biological Marker)A characteristic that is objectivelymeasured and evaluated as an indicatorof normal biologic processes, pathogenicprocesses, or pharmacologic responses toa therapeutic intervention.Biomarker Definitions Working Group –Clin. Pharmacol. Ther. . 69, 2001

SYSYTEMS BIOLOGY APPROACH TOBIOMARKERS RESEARCHBasic ScientistPhysician/ScientistDiscoveryDETECTIONDIAGNOSISValidationBIOMARKERSPREVENTIONResources/ BiorespositoryBioinformaticsTechnology DevelopersPathologist

Capturing the ResponseIntervention/TreatmentBiomarkerSurrogate EndpointObesityIGFBeneficial or Harmful EffectsNot Measured by aBiomarkerClinical EndpointDiabetes

Pathway of DiseaseNatural History of DiseaseTreatment HistoryQualityOf LifeEnvironment+ LifestyleTreatmentOptionsOutcomesDiseaseStagingPatientStratificationGeneticRiskEarlyDetectionBiomarkers

Fundamental Question Remains if Pathologic EvaluationsReflects What Occurs Normally?????

Biomarkers and Other IntermediateIdeal Qualities:• Readily accessible• Easily & reliablyassayed• Differentiallyexpressed• Directly associatedwith diseaseprogression• Modulable• PredictiveEndpointsORGANISMORGANTISSUECELLORGANELLECHROMOSOMEMACROMOLECULEMOLECULE

Multiple Promises and Perils• Many putative biomarkers•few validated•lack of criteria for validation•more clinical studies neededThus biomarkers for disease assessment andearly detection are woefully inadequate

Three Types Biomakers NeededExposure, Effect, SusceptibilityAbsorbedDoseInactive MetaboliteBiologicallyEffective DoseIntake ofDietaryConstituentSusceptibility(Genetic/Environment)EarlyBiologicEffectHealth Effects+ and -AlteredStructure/Function

Numerous Dietary Components MayInfluence HealthEssential Nutrients- Ca, Zn, Se, Folate, C, ENon-EssentialPhytochemicals- Carotenoids, Flavonoids,Indoles, Isothiocyanates, Allyl SulfurZoochemicals - Conjugated linoleic acid, n-3fatty acidsFungochemicals - Several compounds inmushroomsBacteriochemical - Those formed from foodfermentations and those resulting from intestinalflora

Epidemiologic Studies of Soy Components in Diet:Breast Cancer Risk ReductionAsianLee ‘92 (total soy protein).1 .3 .6p < 0.001 PremenopausalNS PostmenopausalHirose ‘95 (beancurd(beancurd, miso)Yuan ‘95 (tofu, soymilk).6 .8 1.0NS Premenopausal.7 1.0 1.3NS PostmenopausalNS p = 0.44–0.79 0.79 Shanghai, TianjinWu ‘96 (tofu).61p < 0.01 Premenopausal.6p < 0.05 PostmenopausalDai ‘01 (soy).46 .66 .95NS All Breast CancerS Just ER + /PR +.25 .44 .78WesternIngram ‘97 (urinary isoflavones).17 .47 1.33NS Diadzein.1 .27 .69p = 0.009 Equolden Tonkelaar ‘01 (urinary.46 .83 1.3phytoestrogens)NS Postmenopausal.79 1.08 1.59Keinan-Boker‘02 (food content).34 .58 .98NS IsoflavonesS Lignans7/12/2005 6:23:26 PM ODAC45 15.6 1.3 2.60 .5 1 1.52Estimated Relative Risk

Promises and Perils for Diet BiomarkersUndeniable limitation inevaluation of eatingbehaviorsUnclear if markers shouldfocus on nutritional statusor dietary intake

Tissue and Leukocyte IQ-DNA AdductsIQ-DNA Adducts (RAL x 10 7 )86420* p

Image courtesy of Nature,issue: Feb. 15, 2001Advances in Genomics Are Significantly Changing Views and Strategies forHealth Promotion and should help identify responders and non-responders

Bronchodilator Response to Albuterol% Responding6050403020100Gly-Gly Arg-Gly Arg-Argβ-2 andrenergic Receptor Genotype (codon 27)Drazen et al , Int Arch Allergy Immunol 124: 183, 2001

The Evolution of Biomarkers ??Gene specificMutationsFunctionalGenomicsFirst GenerationSecondGenerationThirdGenerationFourthGenerationSerumMarkersGeneExpressionProfiles

The “Omics” of Nutrition and Effect BiomarkersBioactiveFoodComponentNutrigenomicsNutrigeneticsNutritionalEpigeneticsNutritionalTranscriptomicsDNARNAProteinPhenotypeProteomicsMetabolomicsMetabolite

Dietary Calcium, VDR FokIGenotype and Colon Cancer RiskOR for Colon Cancer32.521.510.5**Dietary Calcium< 388 mg/day>388 mg/dayP for trend=0.0040FF Ff ffVDR GenotypeWong et al. Carcinogenesis, 24: 1091-1095, 2003

Influence of Caffeine on Bone Mass May Depend on Genes6< 300 mg Caffeine > 300 mg∆ Spine Bone Mass Density (%)0-6-12TT Tt tt TT Tt ttVitamin D Receptor GenotypeRapuri et al. Am J Clin Nutr 2001 Nov;74(5):694-700

Diet-Gene Interactions in Colon CancerPercent survival100908070605040302010p21+/+ AIN-76A Dietp21+/- AIN-76A Dietp21+/+ Western Dietp21-/- AIN-76A Dietp21+/- Western Dietp21-/- Western Diet00 4 8 12 16 20 24 28 32 36WeeksYang et al, Cancer Res. 61, 565, 2001

Nutrigenomics today!• Commercial Nutrition-Gene Test– Genelex Sciona 19 genes includingMTHFR $395– Gene Care CVD nutritional genetic test (SouthAfrica) MTHFR (Hcyst), apoA1 (HDL)+9 others $400• About 30, 000 Genes, 5-8 Million SNPs

Gaps In Science Related to Susceptibility Biomarkers• Large variation ingenetic associations• Studies oftenunderpowered• May require more thanSNPS, i.e.• transcriptomics,proteomics,metabolomics• Confounders notadequately evaluated

% Reduction in LDL Cholesterol as an•Jenkins et al., JAMA 290:502-510, 2003•4 weeks• Statins vs. NCEPStep 2 diet vs. a Portfolioeating plan: plant sterols (1g/1000 kcal) almonds (14 g/1000 kcal) viscous fiber (9.8 g/1000 kcal) soy protein (21.4 g/1000 kcal)Effect Biomarker0-5-10-15-20-25-30-35-8-31-29NCEP Statins Portfolio(20 mg) dietDietary can lower cholesterol as much as cholesterol-lowering drugs

Do Not Over Interpret BiomarkersBiomarkers and Surrogacy: Relevance to Chemoprevention. 2001.Kensler, T.W., Davidson, N.E., Groopman, J.D., and A. Muñoz.

MULTIPLE PATHWAYSEBDMOne Pathway: Attributable Proportion (AP) equals 1Two Pathways: Attributable Proportion equals less than 1AP = S (1-1/R)

MAPPING PATHWAYS AND NETWORKSNahta et al., The Oncologist 2003;8:5-17

• Tomatoes• Spinach• Broccoli• Garlic• Nuts• Salmon• Oats• Blueberries• Green teaTime Magazine: January 21, 2002• Red wine

A Polymeal For Reducing CardiovascularDisease RiskIngredient Amount Possible %ReductionWine 150 ml 32Fish 114g 4X wk 14Dark Chocolate 100g/d 21Fruit/Veg 400g/d 21Garlic 2.7g/d 25Almonds 68g/d 12.5Combined effects 76Franco et al . BMJ (2004) 329: 1447-1450

Components are “complexmixtures” - act synergistically

HCT-116DADSSulindacHCT-15PC-3-+DADS- +DADS- +DADSBottone et al. (2002) J Nutr. 132(4):773-8.

Similar to Drugs One Size Does Not Fit All for theEffects of Diet on Cancer Prevention!Identifying Responders from Non-responders to Bioactive FoodComponents is the Challenge!

ResponseAntioxidantTypicalIntakesImmuneEnhancementCarcinogenMetabolismCell CycleInhibitionApoptosisToxicityNutritionalSupranutritionalExposureToxicModified from Combs and Gray, Parmacol. Ther. 79: 179-192, 1998.

Life Style Issues• What are appropriate assessment atvarious stages in time?• What time is most relevant?• How does diet interact with otherlifestyle factors including exercise?

No Perfect Diet Exists That is:-Desired by everyone-Ideal for everyone healthwise

Nutritional Preemption(A Strategy for Health Promotion)Concept that bioactive foodcomponents can be introducedat points of initiation &progression for pathway leadingto an unhealthy or lethalphenotypeR

When I knew all of life’s answers,they changed all the questions!

Success Will Rest With the ability to:•Identify and validate nutrigenetic,nutritional epigenetic & transcriptomic,proteomic and metabolomic biomarkers ofeffect and susceptibility•Communicate effectively its values to thehealth care community and consumers•Ensure a responsible bioethical framework