““BiomolecularBiomolecularBiomolecularBiomolecularh i fh i fmechanisms of cancer: mechanisms of cancer: 

the clinical perspective”the clinical perspective”Umberto Veronesi, MDUmberto Veronesi, MD

1902Boveri Somatic MutationTheory

1953DNA Double ElixTheory

1969Oncogene Theory1960Philadelphia chromosome

1969Oncogene Theory

1970Reverse transcriptase

1975Monoclonal antibodiesP l Ch i R i

1990Human Project 

1983Polymerase Chain Reaction

1990j

Genoma started

2000Human Genoma project 2000Human Genoma projectconcluded

The DNA within EnvironmentalThe DNA withineach human cell iseach human cell isconstantly exposedconstantly exposedto damaging agents

of bothenvironmental and d i i

Endogenous

endogenous origin.

This scenarioThis scenario necessitates constantnecessitates constant

ill th tsurveillance so thatd d lldamaged cells are 

li i d d deliminated or damagedDNA is repaired.

ENVIRONMENTAL AGENTSENVIRONMENTAL AGENTS

DNA DAMAGE

REPAIR MUTATION

NORMAL CELL CANCER CELLNORMAL CELL CANCER CELL

TheThe knowledgeknowledge onon geneticgeneticThe The knowledgeknowledge on on geneticgeneticalterationalteration ofof cancercancer cellscellsrepresentsrepresents a a fundamental step fundamental step 

dd h fh f ll fftowardstowards the future the future controlcontrol ofofcancercancercancercancer..

ThTh ii blbl ii hhThe The mainmain problemproblem isis the the identificationidentification ofof the morethe moreidentificationidentification ofof the more the more promisingpromising fieldsfields ofof investigationinvestigation..p gp g gg

PREVENTION?PREVENTION?CouldCould the the newnewknowledgeknowledge avoidavoidthe the transformationtransformationff ll llllofof a a normalnormal cellcell

i ti t llll??intointo a a cancercancer cellcell??

DETECTION?DETECTION?DETECTION? DETECTION? C ldC ld ththCouldCould the the newnewvisionvision leadlead toto thethevision vision leadlead toto the the discoverydiscovery ofof aadiscoverydiscovery ofof a a smallsmall focus focus ofofcancercancer cellscells in in anyanypart part ofof the body?the body?

TREATMENT?TREATMENT?TREATMENT?   TREATMENT?   WillWill wewe bebe ableable totoWill Will wewe bebe ableable totoidentifyidentify cellcellidentifyidentify cellcellspecificspecificspecificspecificbiomolecularbiomoleculartargetstargets forfor newlynewlydesigneddesigned agentsagents??

TheThe identificationidentification ofof cancercancerThe The identificationidentification ofof cancercancer‐‐predisposingpredisposing genesgenes isis oneone ofofpredisposingpredisposing genesgenes isis oneone ofofthethe mostmost promisingpromisingthe the mostmost promisingpromisingapproachesapproaches ((PredictivePredictivepppp ((Medicine) Medicine) forfor the the developmentdevelopment ofof programsprogramsi di d ii didiaimedaimed at at preventingpreventing diseasediseaseonsetonsetonsetonset..

CancerCancer‐‐predisposingpredisposingp p gp p ggenesgenes cancan conferconfer upup totogenesgenes can can conferconfer up up toto2020‐‐foldfold increaseincrease ofof2020 fold fold increaseincrease ofofdevelopingdeveloping aa specificspecificdevelopingdeveloping a a specificspecifictypetype ofof tumortumortypetype ofof tumortumor..

(1)(1) MutationsMutations ofofthe the BRCA1BRCA1 and and BRCA2BRCA2 genesgenes, , f df d i 5%i 5% fffoundfound in 5% in 5% ofofbreastbreast cancerscancersbreastbreast cancerscancers, , stronglystronglystronglystronglypredispose predispose totobreastbreast and and ovarianovarian cancercancer. . 

(2)(2) MutationsMutations ofof the the APC APC  and and MYHMYH

li k dli k dgenesgenes, , linkedlinked totothethe developmentdevelopmentthe the developmentdevelopmentofof FamilialFamilialAdenomatousAdenomatousP l iP l iPolyposisPolyposispredisposepredispose totopredispose predispose totocolorectalcolorectal cancercancer. . 

(3)(3) MutationsMutations ofof repairrepairgenesgenes ((MLH1, MSH2 MLH1, MSH2 

d MSH6)d MSH6) li k dli k d ttand MSH6)and MSH6), , linkedlinked totothethe developmentdevelopment ofofthe the developmentdevelopment ofofLynch Lynch SyndromeSyndrome((HereditaryHereditary NonNon‐‐P l iP l i C l t lC l t lPolyposisPolyposis ColorectalColorectalCancerCancer), account), account forforCancerCancer), account ), account forfor5% 5% ofof colorectalcolorectalcancerscancers. . 

HowHow can can wewe exploit exploit thisthis information information totoplanplan anan effectiveeffectiveplanplan anan effectiveeffective

preventionpreventionpreventionprevention??programmeprogramme??

PersonsPersons whowho havehave in in theirtheir DNA DNA mutationsmutations predisposingpredisposing toto specificspecific

ff illill ff “hi h“hi htypestypes ofof cancercancer willwill formform “high “high riskrisk”” groupsgroups in thein the populationpopulationriskrisk   groupsgroups in the in the populationpopulation..

EXAMPLEEXAMPLEEXAMPLE:EXAMPLE:

Women Women withwithBRCA1BRCA1‐‐2 2 mutationsmutationsmaymay bebe submittedsubmittedmaymay bebe submittedsubmittedtoto treatmenttreatment whichwhichtoto treatment treatment whichwhichmaymay reduce the reduce the riskriskyyofof breastbreast cancercancer..

BRCA1BRCA1‐‐2 positive Women2 positive Women

RFenretinide Placebo

and andand andStrict Follow‐up Strict Follow‐up

(MRI l d US) (MRI l d US)(MRI yearly and US) (MRI yearly and US)

Early diagnosis ofEarly diagnosis of cancer may be yimproved by the detection in the blood ofblood of biomolecularbiomolecular markers or even of circulating 

h l i lpathological DNA 

GeneGene expressionexpressionGene Gene expressionexpressionprofilingprofiling hashas beenbeenprofilingprofiling hashas beenbeenexploitedexploited forfor betterbetterexploitedexploited forfor betterbetterprognosisprognosis ofof varyvary typestypesprognosisprognosis ofof varyvary typestypesofof cancercancer avoidingavoidingofof cancercancer avoidingavoidingunnecessaryunnecessary aggressiveaggressiveunnecessaryunnecessary aggressive aggressive treatmentstreatmentstreatmentstreatments..

TheThe discoverydiscovery ofof geneticgeneticThe The discoverydiscovery ofof geneticgeneticalterationsalterations resultingresulting inin specificspecificalterationsalterations resultingresulting in in specificspecificfunctionalfunctional abnormalitiesabnormalities in in cancercancer cellscells hashas led led toto the the developmentdevelopment ofof a a newnew

titi ff t t dt t d ddgeneration generation ofof targetedtargeted drugsdrugsthatthat bear the promisebear the promise ofof higherhigherthatthat bear the promise bear the promise ofof higherhigherefficacyefficacy and and lowerlower toxicitytoxicity. . efficacyefficacy andand lowerlower toxicitytoxicity..

Th fi tTh fi t ll ffThe first The first exampleexample ofoftreatmenttreatment basedbased on aon atreatment treatment basedbased on a on a geneticgenetic somaticsomatic mutationmutationgeneticgenetic somaticsomatic mutationmutationwaswas thethe useuse ofof retinoicretinoic acidacidwaswas the the useuse ofof retinoicretinoic acid acid forfor thethe promyelocyticpromyelocyticforfor the the promyelocyticpromyelocyticleukaemialeukaemia (1990)(1990)leukaemialeukaemia (1990)(1990)

RA destabilizes the PML‐RAR complex, induces terminal differentiation and disease cureinduces terminal differentiation and disease cure

HAT Dnmt

N C R

HDAC

N-CoR

PML

RA

MBD1

RAR

MBD1

RAR A R E

ThTh ff l ll lThe The useuse ofof monoclonalmonoclonalantibodiesantibodies targetingtargetingantibodiesantibodies targetingtargetingaberrantlyaberrantly activatedactivatedaberrantlyaberrantly activatedactivatedsurfacesurface moleculesmolecules hashassurfacesurface moleculesmolecules hashasbecomebecome routineroutine practicepractice ininbecomebecome routine routine practicepractice in in the treatmentthe treatment ofof differentdifferentthe treatment the treatment ofof differentdifferentcancerscancerscancerscancers..

An An exampleexample isis TrastuzumabTrastuzumab((H tiH ti )) l ll l((HerceptinHerceptin), a ), a monoclonalmonoclonalantibodyantibody directeddirected againstagainst thetheantibody antibody directeddirected againstagainst the the HER2HER2 receptorreceptor whichwhich isisHER2 HER2 receptorreceptor, , whichwhich isisfrequentlyfrequently constitutivelyconstitutivelyq yq y yyactivatedactivated asas a a resultresult ofof gene gene amplificationamplification in in breastbreast cancercancer..

Trans-membrane structure of HER-2 receptor

Extracellular domain(632 amino acids)(632 amino acids)Ligand-binding site

Transmembrane domain

Intracellular domain

Transmembrane domain(22 amino acids)Plasma

membraneIntracellular domain(580 amino acids)Tyrosine kinase activity

Cytoplasm

Indicators of increased Indicators of increased HERHER--22

NormalNormal Amplification/OverexpressionHER2 receptor

protein 3HER2mRNA

1

2

4

CytoplasmNucleus

HER2 DNA

4

1 = ↑ gene copy number2 = ↑ mRNA transcription

Cytoplasmicmembrane

Nucleus

3 = ↑ cell surface receptor protein expression4 = ↑ release of receptor extracellular domain

AA goodgood exampleexample ofof a “a “magicmagicA A goodgood exampleexample ofof a a  magicmagicbulletbullet” ” isis ImatinibImatinib ((GleevecGleevec), ), (( ),),whichwhich actsacts byby directlydirectly interferinginterferingwithwith the the tyrosinetyrosine kinasekinase functionfunctionff thth f if i t it i BCR/ABLBCR/ABLofof the the fusionfusion proteinprotein BCR/ABL BCR/ABL 

thatthat isis responsibleresponsible forfor thethethatthat isis responsibleresponsible forfor the the pathogenesispathogenesis ofof chronicchronic myeloidmyeloidp gp g yyleukemialeukemia..

TheThe useuse ofof imatinibimatinib asas wellwellThe The useuse ofof imatinibimatinib, , asas wellwellasas otherother kinasekinase inhibitorsinhibitorsasas otherother kinasekinase inhibitorsinhibitors, , hashas beenbeen extendedextended toto otherotherhashas beenbeen extendedextended toto otherothertypestypes ofof neoplasmsneoplasms thatthattypestypes ofof neoplasmsneoplasms thatthatbearbear activeactive tyrosinetyrosine kinasekinasebear bear activeactive tyrosinetyrosine kinasekinaseactivityactivityactivityactivity..

Examples of targeted treatmentsExamples of targeted‐treatments that have proven clinically activethat have proven clinically active 

Herceptin (Ab anti‐HER2):  Breast Cancer

Tarceva (EFGR inhibitor): Non small Lung CancerTarceva (EFGR‐inhibitor):  Non‐small Lung Cancer

Erbitux (Ab anti‐EGFR): Colon Cancer

Gleevec (bcr/abl‐inhibitor):CML, GIST

A ti (Ab ti VEGF) R l/C l CAvastin (Ab anti‐VEGF): Renal/Colon Cancer

Rituxan (Ab anti‐CD20): Lymphomas( ) y p

Mylotarg (Ab anti‐CD33): Leukemias

Are Are CancerCancer StemStem CellsCells the the nextnext target?target?gg

Anti-proliferative TumorAnti proliferativestrategies

TumorRelapse

Lymph nodes

Primary Carcinoma

No progression

Carcinoma

p g

Progressiong(Clinical

metastases)

Non Cancer stem cells No metastasesNon Cancer stem cells No metastases 

Cancer Stem Cell MetastasesCancer  Stem Cell Metastases

1.1. ConclusionsConclusions1.1. ConclusionsConclusionsThe identification of gene

1.1. Conclusions Conclusions 1.1. Conclusions Conclusions The identification of gene mutations in “germinal cells” willmutations in  germinal cells  willidentify the risk of developing a y p gspecific type of cancer (predictivemedicine) imposing intense 

ti i hi h i kprevention measures in high‐riskpatientspatients.

2.2. ConclusionsConclusions2.2. ConclusionsConclusionsSpecific genetic abnormalitiesh i t t l i thhave an important role in the correct diagnosis of many typescorrect diagnosis of many typesof cancer, improving also theof cancer, improving also the possibility to predict the responseto medical and radiologicaltherapies

33. ConclusionsConclusions33. ConclusionsConclusions

GeneticGenetic mutationsmutations in in cancercancer cellscellsrepresentrepresent a target a target forfor specificspecifictiti l ll l SS ttanticanceranticancer moleculesmolecules. Some . Some typestypes

ofof cancerscancers havehave alreadyalready beenbeen putputofof cancerscancers havehave alreadyalready beenbeen put put under under controlcontrol and and forfor othersothers the the expectationsexpectations are are realisticrealistic. . 

4. Conclusions4. ConclusionsHH itit tt bb kk th tth t thth

4. Conclusions4. ConclusionsHoweverHowever itit mustmust bebe knownknown thatthat the the researchesresearches on DNA and on theon DNA and on theresearchesresearches on DNA and on the on DNA and on the developmentdevelopment ofof a a biomolecularbiomolecularppdrugsdrugs are are highlyhighly expensiveexpensive: the : the costscosts willwill bebe prohibitiveprohibitive forfor a a goodgoodportionportion ofof the worldthe worldportionportion ofof the worldthe world

5. Conclusions5. Conclusions5. Conclusions5. Conclusions

AllAll thisthis maymay leadlead toto a a furtherfurther gap gap betweenbetween richrich and and poorpoor CountriesCountries. . AA ll i i li i l lili b db dA A novelnovel internationalinternational policy, policy, basedbasedonon solidaritysolidarity isis neededneeded toto allowallowon on solidaritysolidarity isis neededneeded, , toto allowallowallall world world populationpopulation toto havehavep pp paccessaccess toto the the newnew drugsdrugs..

The futureThe futureThe futureThe futureHave the expectations of the years 2000 been fulfilled?Th i di t bThe immediate answer may be“NO” because cancer is stillNO  because cancer is stillthere and 10 million people diep pevery year for the disease.

WeWe havehave immenselyimmensely improvedimproved ourourknowledgeknowledge on the natureon the nature ofof cancercancerknowledgeknowledge on the nature on the nature ofof cancercancerWeWe havehave nownow a a clearclear maproadmaproad totofuture future solutionssolutions

THEREFORETHEREFORETHEREFORETHEREFORETheThe honesthonest andand realisticrealistic answeranswerThe The honesthonest and and realisticrealistic answeranswer

isis “NOT YET”“NOT YET”