TERAPIA BLANCO

Dr. Roberto Iván LópezInstituto Oncológico Nacional

Panamá, Republica de Panamá

Farmacogenómica

Historia de la Medicina

Terapia Blanco

Normal epithelium

Pre-cancerousstates

Carcinoma Metastasis

Muta

tion 1

Mutation 2

Mutation 3

Mutation 4

Serial mutations lead to cancer, but reversing any one step will inhibit tumours

0 5 100 5 10

Años de Crecimiento*

Años de Crecimiento*

Cáncer de Mama muy temprano (indetectable)Cáncer de Mama muy

temprano (indetectable)

Nu

mer

o d

e cé

lula

sN

um

ero

de

célu

las

Número de Doblajes de CélulasNúmero de Doblajes de Células

0 5 10 15 20 25 30 35 400 5 10 15 20 25 30 35 40

1012

1010

108

106

104

102

1012

1010

108

106

104

102

1 mm1 mm

1 cm1 cm

10 cm10 cm

DCISDCIS

Cáncer de Mama Clínico

Cáncer de Mama Clínico

DCIS = Carcinoma Ductal in situ.*Nota: doblaje de 90-días doblaje de 40 = 3,600 días (approximadamente 10 años).Harris JR, et al, eds. Breast Diseases, 2nd ed. Philadelphia: JB Lippincott; 1991:165-189.

DCIS = Carcinoma Ductal in situ.*Nota: doblaje de 90-días doblaje de 40 = 3,600 días (approximadamente 10 años).Harris JR, et al, eds. Breast Diseases, 2nd ed. Philadelphia: JB Lippincott; 1991:165-189.

Progresión del Cáncer de MamaProgresión del Cáncer de Mama

agente anticancer

ideal

La terapia ideal debe atacar solo a las celulas

neoplasicas

Beneficio Sobrevida

Alta actividad antitumoral

Control de Sintomas

Mejoria QoL

No toxicidad irreversible

No efectos sec. corto plazo

Administracion conveniente

Costo-efectividad

Terapia anticancer “ideal”

“We used to think our fate was in our stars. Now we know, in large

measure, our fate is in our genes”

J.D Watson. Time Magazine 20 March 1989

WNT

Cell

ECM

Growth factors (e.g. EGF, amphiregulin TGF)

Nuclear receptors(e.g. oestrogen)

Survival factors(e.g. IGF1)

Cytokines(e.g. ILs, IFNs)

Deathfactors

(e.g. FasL)

Anti-growth factors(e.g. TGF)

GPCR ligands

Frizzled Dishevelled

GSK-3

APC

Tubulin

TCF

Integrins

-Cutenin -Cutenin:TCFE-Cadherin

CdC42 PI3K Rac

FakCas Crk

Src

Fyn

ShcNF1

RasRTK Grb2SOS

Ral MEK MAPK MAPK

MEKK

PLC

PKC Mos MKKs JNKs

ELK

Myc:Max

Max:MaxFos

JUN

Abl

7-TMR

CdC42 Rac Rho

G-Prol Ad Cycl PKA CREB

PKC NF-B

NHR (e.g. ER)

NF-B

P13K Akt Akka IKB

PTEN?

Stat 3.5

Stat 3.5

Stat 3.5

Bcl XL

Caspase 9

Cytochrome C

Jaks

Bad BidMitochondria

Bim, etc.Abnormalitysensor

Bcl-2

Cell Death(Apoptosis) Caspase 8

Fap

FADD

Bcl-2

Bax

ARF

p53

Mitochondria

MDM2

DNA damagesensorCell

Proliferation(cell cycle)

Changesin Gene

Expression

Cycl E:CDK2 p21

p27

E2Fs

Rb

p16

Cycl D:CDK+ p15 Smads

RTK

Cytokine R

Decoy R

Fas

SurfaceAg

TGFR

HPVE7

Hanahan D, Weinberg RA. Cell 2000;100:57–70

Como trasladar las interacciones moleculares complejas en beneficio clinico

Que es Terapia Blanco?

Terapia Blanco

• Características especificas de las células

• Diferencias entre célula normal y cáncer– Terapia dirigida– Disminuir efectos secundarios

• Componentes internos de la célula– Pequeñas moléculas (TK)

• Receptores en la superficie de la célula– Anticuerpos moleculares (MoAb)

• Vasos sanguíneos– Terapia antiangiogenica (VEGF)

Terapia Blanco

Mecanismo de Acción

Señal detransducción

al núcleo

Núcleo

Sitio de unión

Actividad deTirosina kinasa

Citoplasma

MembranaPlasmática

Factor de Crecimiento

Activación del genDIVISIONCELULAR

TK inhibitors

Intracellular targeting

Membrane

Extracellular

Intracellular

TK

R

TK

EGFR Growth Factor Signaling

Membrane

Extracellular

Intracellular

TK

R

TKTK

R

TK

EGFR Growth Factor Signaling

Membrane

Extracellular

Intracellular

TK

R

TK TK

R

TK

pY pY

pY pY

pY pY

TK

R

TK

EGFR Growth Factor Signaling

Membrane

Extracellular

Intracellular

Signaling molecules

TK

R

TK TK

R

TK

pY pY

pY pY

pY pY

Substrate

SubstratepY

TK

R

TK

EGFR Growth Factor Signaling

Membrane

Extracellular

Intracellular

Signaling molecules

TK

R

TK TK

R

TK

pY pY

pY pY

pY pY

Substrate

SubstratepY

TK

R

TK

EGFR Growth Factor Signaling

Membrane

Extracellular

Intracellular

Signaling molecules

Cellular effects e.g., + Growth + Proliferation - Apoptosis

TK

R

TK TK

R

TK

pY pY

pY pY

pY pY

Substrate

SubstratepY

TK

R

TK

+Angiogenesis

EGFR Growth Factor Signaling

• Several types of TK inhibition

– single inhibition: highly selective inhibition of one HER TK

– dual inhibition: inhibition of two HER TKs (e.g. HER1 and HER2)

– pan-HER-TK inhibition: block the TK activity ofall the members of the HER family

– reversible or irreversible inhibition

Small molecule HER-TK inhibitors

Agent Irreversible Target Tumour type Stage

Gefitinib No HER1 NSCLC, H&N, prostate

Marketed

TarcevaTM No HER1 NSCLC, H&N, ovarian Phase III

GW2016 No HER1/2 Breast Phase III

CI-1033 Yes Pan HER SCC, skin Phase II

EKB-569 Yes HER1 Colon Phase II

AEE-788 No HER1/2 – Phase I

Adapted from Mendelsohn J, Baselga J. J Clin Oncol 2003;21:2787–99

TK inhibitors designed to target the HER family

• Highly selective, potent and reversible HER1/EGFR-TK inhibitor – can inhibit EGFRvIII mutant

• Orally available

• Competes with ATP for binding to the TK domain of the receptor– prevents TK phosphorylation

– abrogates the receptor’s catalytic activity

Cell-cycle progression Angiogenesis Apoptosis Output

TarcevaTM

• Anti-HER monoclonal antibodies (MAbs)

Extracellular targeting

Adapted from Mendelsohn J, Baselga J. J Clin Oncol 2003;21:2787–99

Agent Characteristic Target Tumour type Stage

Herceptin® Humanised HER2 Breast, gastric, bladder

Marketed

OmnitargTM Humanised HER2 Breast, ovarian, prostate, NSCLC

Phase II

Cetuximab Chimaeric HER1 Colon, H&N Phase III

MDX-447 Bispecific HER1/CD64 Phase II

h-R3 Humanised HER1 Phase II

EMD-7200 Humanised HER1 H&N Phase I

ABX-EGF Human HER1 Renal Phase I

MAbs designed to target the HER family

• Humanised IgG1 monoclonal antibody

• Targets HER2– antagonism of constitutive growth signalling

properties– induces antibody-dependent cell-mediated

cytotoxicity (ADCC)– leads to internalisation and degradation– downregulation reduced number of

HER2-containing heterodimers

Cell-cycle progression Angiogenesis Apoptosis Output

Herceptin®

Normal HER2 expression

HER2 amplification leads toHER2 overexpression

HER2 overexpression leads totumour proliferation

Binding of Herceptin® to HER2

• Chimaeric IgG1 monoclonal antibody

• Targets HER1/EGFR

• Competitive binding, blocking natural ligand– blocks TGF-activation of EGF– prevents receptor phosphorylation – downregulation of receptor

Cell-cycle progression Angiogenesis Apoptosis Output

Cetuximab

Tumor cell

Capillary

Terapia Antiangiogenica

VEGF

Angiogenesis

Avances en el Tratamiento del Cáncer Terapia Antiangiogenica

Tumor cell

Vascularization

Avances en el Tratamiento del Cáncer Terapia Antiangiogenica

VEGF

Blebbing of

endothelial cell

VEGF receptor

Avances en el Tratamiento del Cáncer Terapia Antiangiogenica

Regressingvasculature

Shrinkingtumor cell

Avances en el Tratamiento del Cáncer Terapia Antiangiogenica

Radiotherapy

Hormonal therapy Chemotherapy

Biologicaltherapies Herceptin®

TarcevaTM

AvastinTM

OmnitargTM

Tumour type

Disease stageMolecular phenotype

Tumour genotype

Treatment

Molecular characterisation will enable more individualised treatment

“ It is much more important to know what kind of patient has a disease, than to know what kind

of disease a patient has”

Caleb Parry. 18th Century physician, Bath.

TolerabilityTolerability

Patient’s preferences

Patient’s preferences Impact on QoLImpact on QoL

Efficacy

ConvenienceConvenience

Factors driving treatment decisions

Age

Performance status

Patient history

Patient preference

Comorbiditiese.g. diabetes, impaired

cardiac function

Sites Pace ofrelapse

Previoustherapy

Fitness

Cardiacfunction

Renal/hepaticfunction

Patient characteristicsinfluence treatment decisions

Nuevas Terapias Blanco en Oncologia

MetastasesInhibitors

EGFRinhibitors

HIFinhibitor MEK

inhibitors

mTORinhibitors

HDACInhibitors

Kinesins

FarnesylTransferaseInhibitors

Anti-Angiogenesis

Rafinhibitor

Srcinhibitor

IGF-1Rinhibitors

Cell Cycleinhibitors

Proteasomeinhibitor

Aurora Kinaseinhibitor

Mdm2inhibitor

Tubulin-interacting

agents

MUC-1Directed

antibodies

HER2-Rinhibitors

Pro-apoptoticdrugs

HSP90inhibitors

Death Receptors