INTODUCTION

TOCLINICALONCOLOGY

2

AGENDA

¡ CHEMOTHERAPY

¡ ENDOCRINETHERAPY

¡ TARGETEDTHERAPIES

¡ PERSONALIZATIONOFONCOLOGY

¡ IMMUNOTHERAPY

3

18_02_four_phases.jpg

Synthesis of DNA

precursors, proteins, etc.

Premitotic synthesis of

structures

CellCyclePhases

4

UncontrolledProliferation

¡ Resultofactionofproto-oncogenesorinactivatedtumorsuppressorgenes

¡ Changeingrowthfactors,receptors

¡ increasedgrowthfactorsproduction

¡ Changeingrowthfactorpathways

¡ Changeincellcycletransducers

¡ Cyclins,Cdk’s,Cdkinhibitors

5AnticancerDrugsare

Antiproliferative

¡ Affectcelldivision

¡ Activeonrapidlydividingcells

¡ MosteffectiveduringSphaseofcellcycle

¡ ManycauseDNAdamage

¡ DamageDNAà initiationofapoptosis

6

¡Sideeffectsgreatestinotherrapidly-dividingcells

¡ Bonemarrowtoxicity

¡ Impairedwoundhealing

¡ Hairfollicledamage

¡ GIepiteliumdamage

¡ Growthinchildren

¡ Gametes

¡ Fetus

¡Maythemselvesbecarcinogenic

7DifficultiesinChemotherapy

Effectiveness

¡ Solidtumors

¡ Growthratedecreasesasneoplasmsizeincreases

¡ OutgrowsabilitytomaintainbloodsupplyAND

¡ Notallcellsproliferatecontinuously

¡ Compartments

¡ Dividingcells(maybe~5%tumorvolume)

¡ Onlypopulationsusceptibletomostanticancerdrugs

¡ Restingcells(inG0);canbestimulatedà G1

¡ Notsensitivetochemotherapy,butactivatedwhentherapyends

¡ Cellsunabletodividebutaddtotumorbulk

8

DrugsUsedinCancerChemotherapy

¡CytotoxicAgents

¡ AlkylatingAgents

¡ Antimetabolites

¡ Cytotoxicantibiotics

¡ Plantderivatives

9

Rand 50.3

10

Rang 50.4

11

Antimetabolites

¡ Mimicstructuresofnormalmetabolicmol’s

¡ InhibitenzymescompetitivelyOR

¡ Incorporatedintomacromoleculesà inappropriatestructures

¡ KillcellsinSphase

¡ Threemaingroups

¡ Folateantagonists

¡ Pyridineanalogs

¡ Purineanalogs

12

13

M

G2

G1

S

CyklinBCDK1

CyklinACDK1

Cylin E1,E2CDK2

CyklinD1,D2,D3CDK4CDK6

p15,p16,p18,p19

p21,p27,p57

supressors ofeRb

p21,p27,p57

p21,p27,p57

ENDOCRINETHERAPY

CDK4/6INHIBITORS

PJW

ER,PR,ARPI3K/AKT

RAS/RAF/MAPKWNT/βcatenin

NF-κB

RB/E2F

14ROUTESOFCHEMOTHERAPY

ADMINISTRATION

¡ INTRAVENOUS

¡ ORAL

¡ ANTIMETABOLITES

¡ ALKYLATINGAGENTS

¡ MITOTISSPINDLEPOISONS

¡ INTRAPERITONEAL

¡ INTRATUMORAL(TRANSARTERIALCHEMOEMBOLIZATION)

15HIPECHYPERTHERMIC

INTRA-PERITONEAL

CHEMOTHERAPY

16TRANSARTERIAL

CHEMOEMBOLIZATION

17

Case Example 1: Chemoembolization of Hepatocellular Carcinoma

This 60 year-old cirrhotic female has a 3 cm mass in

the posterior right segment of the liver diagnosed on

pre-procedure CT scan (1a arrow). She was referred

for chemoembolization. The arteriogram demonstrates

the targeted mass (1b arrow). Follow-up imaging

demonstrates complete tumor necrosis (1c arrow).

The patient went on to liver transplant 6 months later.

1818

ENDOCRINE

THERAPY

19

Hormones

¡ Tumorsderivedfromtissuesrespondingtohormonesmay

behormone-dependent

¡ GrowthinhibitedbyhormoneantagonistsORotherhormones

w/opposingactionsORinhibitorsofrelevanthormone

¡ Glucocorticoids

¡ Inhibitoryonlymphocyteproliferation

¡ Usedagainstleukemias,lymphomas

20¡ ESTROGENRECEPTOR

¡ breast,ovarian,endometrialcancers

¡ drugs

¡ ERblockers– tamoxifen,fulvestrant

¡ estrogensynthesisblockers– aromataseinhibitors

¡ estrogendeprivation– aGnRH agonists/antagonists

¡ ANDROGENRECEPTOR

¡ prostate,breastcancer

¡ drugs

¡ androgendeprivation– aLHRH agonists/antagonists

¡ ARblockers– flutamide,bikalutamide,enzalutamide

¡ androgensynthesisblocker– abiraterone

¡ PROGESTERONERECEPTOR

¡ specificdrugsindevelopment

¡ progestogens

21

ERER

E

ENDOCRINETHERAPYINBREAST

CANCER

PJW

22

CoAAP-1 TFs

ERER CoAER CoA

E

PROLIFERATIONSURVIVAL

METASTASESCHEMORESISTANCE

PJW

23

ERERERER

MAPK AKT

RAS PI3K

CoAAP-1 TFs

CoA CoA

CoASrc

E

RAS PI3K

AKTMAPK

HER2,EGFR,IGF1-R

PROLIFERATIONSURVIVAL

METASTASESCHEMORESISTANCE

PJW

24

ERERERER

MAPK AKT

RAS PI3K

CoAAP-1 TFs

CoA CoA

CoASrc

SERMFULW.

E

IA

RAS PI3K

AKTMAPK

HER2,EGFR,IGF1-R

PROLIFERATIONSURVIVAL

METASTASESCHEMORESISTANCE

PJW

ERER

ER

ERSERMFULW.

25

HYPOTHALAMUS

PITUARYGLAND

GONADOTROPINRELEASINGHORMONES

LH,FSH

TESTOSTERONE NEGATIVEFEEDBACKLOOP

GONADOLIBERIN•AGONISTS• ANTAGONISTS

ANTIANDROGENS ANDROSTENDIONEDHEA

MALEENDOCRINESYSTEM

26HORMONESENSITIVITYOF

PROSTATECANCER

27HORMONESENSITIVITYOF

PROSTATECANCER

SURVIVAL

PROLIFERATION

ANGIOGENESIS

METASTASIS

28ENDOCRINETHERAPYOF

PROSTATECNACER

ANTIANDROGENSFLUTAMIDE

BIKALUTAMIDE

castrationsurgicalpharmacologicalaGnRH

29RESISTANCETOCASTRATION

AUTOCRINEPRODUCTIONOF

ANDROGENS

AUTOCRINEPRODUCTION

OFANDROGENS

SURVIVAL

PROLIFERATION

ANGIOGENESIS

METASTASIS

30RESISTANCETOCASTRATION

ARamplification

SURVIVAL

PROLIFERATION

ANGIOGENESIS

METASTASIS

31RESISTANCETOCASTRATION

ARoverexpression

SURVIVAL

PROLIFERATION

ANGIOGENESIS

METASTASIS

32RESISTANCETOCASTRATION

hypersensitivity ofAR

SURVIVAL

PROLIFERATION

ANGIOGENESIS

METASTASIS

33

RESISTANCETOCASTRATION

co-regulators

SURVIVAL

PROLIFERATION

ANGIOGENESIS

METASTASIS

34

RESISTANCETOCASTRATION

activationofARbyotherfactors¡ prolactin

¡ growthhormone

PRZEŻYCIE

PROLIFERA

CJA

ANGIOGEN

35RESISTANCETOCASTRATION

activationofARviavarious

signallingpathways¡ IGF-1

¡ KGF

¡ TGF

¡ IL-6

¡ IL-8

IGF-1RKGFR

EGFR

IL-6R

HER2

SURVIVAL

PROLIFERATION

ANGIOGENESIS

METASTASIS

36

Rang 50.1

Antitumor Agents Working through Cell Signalling

37

¡ Cetuximab,Panitumumab

¡ MonoclonalAbdirectedagainstEGFR

¡ Erbitux–anti-EGFRAb

Drugs Targeting Growth Factor Receptors

38¡ Trastuzumab

¡ Humanized mousemonoclonalAb

¡ BindsHER2

¡ Membraneproteinstructurallysimilar

toEGFR

¡ Hasintegraltyrosinekinaseactivity

¡ Importantinbreastcancercells

¡ Mayalsoinducep21andp27

¡ Cellcycleinhibitors

http://www.gene.com/gene/products/information/oncology/herceptin/images/moa.jpg

39

PERSONALIZEDHEALTHCAREIN

ONCOLOGY

- WEARENOTTHEREYET-

40

CANCER

CANCER

CANCER

CANCER

CANCER

CANCER

41

TailoringTreatment?¡ „IfIgotomytailortobuyanewsuit,IdonotaskforasuitforagroupofCaucasianmenwithwhite hair–

- Iexpecttobemeasuredforthesuitsothatitfitsmealone

¡ It’simportanttodifferentiatebetweentreatmentthatistailoredindividually….

….andtreatmentthatistailoredtoagroup(e.g.womenwithbreastcancerwhosecellsexpressHER2)”

prof. Ian Tannock

PMH University of Toronto

42

BIOMARKERS

BIOMARKER=BIOLOGICALMARKERTHATCANBEDEFINEDON

GENOMICORMOLECULARLEVEL

- BIOLOGICALPROGNOSTICFACTORS

- BIOLOGICALPREDICTIVEFACTORS

- BIOLOGICALSIGNSOFTREATMENTEFFICACY

(RESPONSE)

- BIOLOGICALMARKERSDEMONSTRATINGRESISTANCE

TOTREATMENT

4343

NOVELantiangiogenic

THERAPIES–arethereanybiomarkers?

44

DISTANTMETASTASES

VEGFR

PDGFR

45

BEVACIZUMAB

INHIBITIONOFANGIOGENESIS

VEGFR/PDGFRINHIBITORSSUNITYNIB,SORAFENIB,EVEROLIMUS

46

BEVACIZUMAB

VEGF– KEYFACTORINTUMOR-INDUCEDANGIOGENESIS

VEGF– IMMUNOSUPRESIVEFACTOR

VEGF– PROGNOSTICFACTOR

BUT

VEGF–PREDICTIVEFACTORFORBEVACIZUMABEFFICACY???VEGF-A,VEGF-B,VEGF-C,VEGF-D,VEGF-E,PlGF,sVEGFR??

47ANTIANGIOGENICTHERAPIESUSEDFORTREATMENTOFRENALCANCER

TYROSINEKINASEINHIBITORS

• SORAFENIB– VEGFR-1,VEGFR-2,VEGFR-3, PDGFR-b,RAF• SUNITYNIB– VEGFR-1,VEGFR-2,VEGFR-3,PDGFR-a,PDGFR-b

SERINE-THREONINEKINASE(mTOR)INHIBITORS

• TEMSIROLIMUS• EVEROLIMUS

VEGFNEUTRALIZATION

• BEVACIZUMAB

BUTTHEREISNOSINGLEPREDICTIVEFACTOR

4848

HER2AND

TARGETED

THERAPIES

INBREASTCANCER

49HER2(ErbB2)MEMBEROFEPIDERMALGROWTHFACTORRECEPTORFAMILY

- OVEREXPRESSIONOFHER2– prognosticbiomarkerinbreast

cancer

- OVEREXPRESSIONOFHER2– negativepredictivebiomarkerfor

responsetohormonaltreatmentinbreastcancer

- OVEREXPRESIONOFHER2– predictivebiomarkerfortherapies

targetingthisreceptor(trastuzumabandlapatinib)

50HER2PROGNOSTICBIOMARKER

INBREASTCANCERPATIENTS

1,00

0,75

0,50

0,25

0Over

all

su

rviv

al

pro

bab

ilit

y

0 2 4 6 8 10 12

HER2 overexpression

years

HER2 standard level

51HER2– PREDICTIVEBIOMAKEROF

TRASTUZUMAB(Herceptin)EFFICACYB-31i N9831 – combinedanalysis

94%

91%

87%

92%

80

70

60

50

90

HR=0,67; p=0,015

ACàPHACàP

16721679

6292

n Deaths

years1 2 3 4 50

Overallsurvivalprobab

ility

52THEREALEFFICACYOF

TRASTUZUMAB

¡ INMETASTATICBREASTCANCER(MBC),RESISTANCETOTRASTUZUMABMONOTHERAPY– 66-88%

¡ THEMAJORITYOFMBCPATIENTSPRIMARILYRESPONDINGTOTRASTUZUMABWILLDEVELOPRESISTANCEWITHIN1YEAR

¡ INADJUVANTTREATMENT– DISSEMINATIONOFDISEASEWILLOCCURIN~15%OFPATIENTS

Nahta R.Breast Cancer Res,2006

5353

ATTHECELL

MEMBRANEHER2ANDRESPONSETOTRASTUZUMAB

54

TRASTUZUMABINHER2-OVEREXPRESSINGBREASTCANCER

HER2 HER2 EGFR

TK

trastuzumab trastuzumab

PROLIFERATION,INVASION,METASTASING,ANGIOGENESIS

RAS

RAF

MEK

ERK

PI3K

AKT

mTOR

HER2 HER2

55

TYROSINEKINASE

Trastuzumab

MONOCYTE

FcγR

56

EFFICACYOFTRASTUZUMABMAYDEPENDONFcγRGENEPOLYMORPHISM

57

Loss ofextracellular domainofHER2receptor

?

p95

58

OverexpressionofMUC4 ?

59

??

?

?

?

?

6060

INSIDETHECANCER

CELLHER2ANDRESISTANCETOSYSTEMICTREATMENT

61

6262

EVALUATIONOF

RESPONSETO

TREATMENTTARGETEDTHERAPIES– RESPONSETOTREATMENT

6363TRASTUZUMAB– CYTOSTATICBUTALSOCYTOTOXICDRUG– EVALUATIONOFRESPONSETOTREATMENTISOBJECTIVEANDQUITESIMPLE

BUT

INTHECASEOFNOVELANTIANGIOGENICTARGETEDTHERAPIES– BEVACIZUMAB,SORAFENIB,SUNITYNIB,TEMSIROLIMUS,EVEROLIMUS…Thesamesize oftumorfollowing 4months oftreatment –noresponse?

ALMOST95%OFTUMOR– NECROSIS- BIOMARKERSOFRESPONSEAREEXTREMELYHELPFUL-

6464

TOXICITYAND

PATIENTS’SELECTIONTARGETEDTHERAPIES

65ADVERSEEVENTSASSOCIATEDWITH

TARGETEDTHERAPIES¡ MYELOSUPRESSION

¡ HEARTFAILURE

¡ HYPERTENSION

¡ HYPOTHYROIDISM

¡ IMMUNOSUPRESSION

¡ DERMATOLOGICDISORDERS

¡ AUTOIMMUNOLOGICALDISORDERS

¡ ANAPHYLAXIS,ALLERGICREACTIONS

¡ ELECTROLYTEIMBALANCE

¡ HEMORRHAGE

¡ THROMBOEMBOLICEVENTS

¡ NEUROPATHY

¡ IMPOTENCE

¡ INTESTINALPERFORATION

¡ MUSCLECRAMPS

¡ PERIPHERALOEDEMA

?

?? ? ? ?

?

??

???

66

ACRUCIALPOINTINCLINICALONCOLOGY

EARLYDETERMINATIONOFRESISTANCETOTREATMENT

WHENAPARTICULARDRUGISSTILLADMINISTERED

?????????????????

CIRCULATINGTUMORCELLS

67GENOMICANDPROTEOMICANALYSISOFCIRCULATINGTUMORCELLS-INTELIGENCESERVICEINONCOLOGY-

6868

TARGETEDTHERAPIES– STRIKE

ONAWELL-KNOWNENEMYFROMAHISTORICALPOINTOFVIEW

69CHEMOTHERAPY

70TARGETEDTHERAPIES

71

TOKNOWWHERE,WHENANDHOW

WECANTARGETTHEENEMY(CANCERCELLS)

BUT IN ORDER …

INORDERTOBEPREPAREDONA

COUNTERSTRIKE

WENEEDALOTOFINTELDATA!!!!

72WENEED

APERFECTINTELLIGENCESERVICE

73

7474

IMMUNOTHERAPY

75PIERWSZE PRÓBY IMMUNOTERAPII

1893– WilamBColey,NewYork–

case reportonspontaneous

regression advanced sarcoma inapatient

following ahighfever fromerisipelas infection

1895– First’trials’onimmunotherapy –

subcutaneous injection ofstreptococcus pyogenes topatients withadvanced

tumors toprovoke immune response

MECHANISMOFACTION– RAPIDINFLAMMATORYREACTION– ”CYTOKINE

STORM”LEADINGTOREACTIVATIONOFSUPPRESSEDIMMUNERESPONSES.

COLEY’STOXININDUCEDPRODUCTIONOFTNFα

PFIZERCONTINUESDEVELOPMENTOFCOLEYTOXIN

BEGINNINGOFIMMUNOTHERAPY75

7676

77

78

LIMFOCYTT

COSTIMULATORYRECEPTORS

MHCICD28IL-12RIL-2R

ODPOWIEDŹIMMUNOL.

IMMUNOSUPPRESSIVEMOLECULES

CTLA4PD-1

PD-L1

IMMUNEHOMEOSTASISMECHANISMSTHEKEYTOCANCER-INDUCEDIMMUNOSUPPRESSIONCHECKPOINTS

78

ANTI-CTLA4

IPILIMUMAB

ANTI-PD1

NIVOLUMAB

PEMBROLIZUMABANTY-PDL1

ATEZOLIZUMAB

7979

CHECKPOINTINHIBITORS

THEBREAKTHROUGHIN

CLINICALONCOLOGY

8080

81IPILIMUMAB (ANTI-CTLA4)

OVERALLSURVIVAL

Hodi SF NEJM 2010

23%

IPI – mediana follow-up (27 mies.)

82ADVANCEDMELANOMA

OVERALLSURVIVAL

IPILIMUMABvs HISTORICALCONTROL

Korn ELiwsp.JCO2008

Schadendorf Diwsp.ESMO2013

83

Patients at Risk

Ipilimumab 4846 1786 612 392 200 170 120 26 15 5 0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 12 24 36 48 60 72 84 96 108 120

Ipilimumab

CENSORED

N:4846

Median OS, months. (95% CI): 9.5 (9.0–10.0)

3-year OS, % (95% CI): 21 (20–22)

Pro

porti

on

Ali

ve

Months

Schadendorf Diwsp.ESMO2013

84

85

86

8787

ANTI-PD1/ANTI-PD-L1

CHECKPOINTINHIBITORS

88

PD-1– PD-L1– MECHANISMOFIMMUNOSUPPRESSION

MHCI

activated

specific Tcell

CANCERCELL

TCR

PD-1 PD-L1

89anti-PD1– MECHANISMOFACTION

MHCITCR

PD-1 PD-L1

activated

specific Tcell

CANCERCELL

90

MHCITCR

PD-1 PD-L1

ANTI-PD-L1– MECHANISMOFACTION

activated

specific Tcell

CANCERCELL

91CHECK-POINTINHIBITORS

APPROVED2014-2016

¡ ANTI-PD1

¡ MELANOMA

¡ SQUAMOUSNON-SMALLCELLLUNGCANCER

¡ NON-SQUAMOUSNON-SMALLCELLLUNGCANCER

¡ RENALCELLCANCER

¡ HODGKINLYMPHOMA

¡ ANTI-PDL1

¡ BLADDERCANCER

EXPECTEDAPPROVAL– COLRECTALCANCER,HEAD&NECK

CANCER,BLADDERCANCER,BREASTCANCER,

9292

ONCOLYTIC

VIRUSES

93

E1

E1b

E.G. „WILD” ADENOVIRUS INFECTS A TARGET CELL

PRODUCT OF THE E1 VIRAL GENE

PREVENTS TP53-MEDIATED APOPTOSIS OF INFECTED CELL

94

ADENOVIRAL REPLICATION IN THE INFECTED CELL

95

LYSIS OF THE INFECTED CELL AND RELEASE

OF VIRAL PARTICLES AND TUMOR ANTIGENS

96

REPLICATED VIRUSES INFECT ADJACENT CELLS

97T-VEC– NOVELIMMUNOTHERAPYBASED

ONONCOLYTICHSV– APPROVEDIN

MELANOMA

98T-VEC