Targeted 1

Terapia dirigida (Targeted) en Oncología

Navigating Multiple Pathways: Targeted Therapies

Temario  VEGF  VEGF-Plus  EGFR  Bcr/abl, c-Kit, PDGF  HER2  CD 20

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Medicamentos antiangiogénicos

Papel del VEGF en cáncer

Navigating Multiple Pathways: Targeted Therapies

VEGF: Un Mediador Clave de Angiogenesis Aumento de los niveles de VEGF

Genes implicados en tumorogénesis (p53, p73, src, ras, vHL, bcr-abl)

Factores ambientales (hipoxia, pH)

Factores de crecimiento, Hormonas (EGF, bFGF, PDGF, IGF-1, IL-1α, IL-6, estrogen)

bFGF, basic fibroblast growth factors; EGF, epidermal growth factor; IGF, insulin-like growth factor; IL, interleukin; PDGF, platelet-derived growth factor; VEGFR, VEGF receptor. 1. Dvorak HF. J Clin Oncol. 2002;20:4368-4380; 2. Ebos JM, et al. Mol Cancer Res. 2002;1:89-95; 3. Ferrara N, et al. Nat Med. 2003;9:669-676. clinicaloptions.com/oncology

Navigating Multiple Pathways: Targeted Therapies

VEGF: Un Mediador Clave de Angiogenesis Unión y activación del VEGFR

VEGF P P

PLC PKC

PI3-K IP3

Survival

AKT

P P

FAK

Ras

Paxillin

Proliferation

Activación de la célula endotelial

MAPK

Migration

ANGIOGENESIS

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La familia VEGF y sus receptores PIGF

VEGF-A

VEGFR-1 (Flt-1)

VEGF-B

VEGF-C

VEGFR-2 (Flk-1/KDR)

Angiogenesis

Neufeld G, et al. FASEB J. 1999;13:9-22.

Angiogenesis Linfangiogénesis

VEGF-D

VEGFR-3 (Flt-4)

Linfangiogénesis

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Modelos preclínicos de MOAs contra VEGF  Pueden causar regresión de la microvasculatura1,2  Normalizan la vasculatura madura que sobreviven3-5  Puede inhibir el re-crecimiento de los vasos y la neovascularización2,3,6

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Atacando al VEGF: La historia del Bevacizumab Bevacizumab VEGF

P P

P P

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Navigating Multiple Pathways: Targeted Therapies

Atacando al VEGF: La historia del Bevacizumab Bevacizumab VEGF

P P

P P

BLOQUEO de la activación del VEGFR clinicaloptions.com/oncology

Navigating Multiple Pathways: Targeted Therapies

Actividad clínica del Bevacizumab  Carcinoma colorrectal  Carcinoma de células renales  Carcinoma de pulmón – células no pequeñas  Carcinoma de mama  Glioblastoma multiforme

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Navigating Multiple Pathways: Targeted Therapies

Trampa VEGF (VEGF Trap)

P P

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Navigating Multiple Pathways: Targeted Therapies

VEGF Trap

P P

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Navigating Multiple Pathways: Targeted Therapies

VEGF Trap

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Navigating Multiple Pathways: Targeted Therapies

VEGF Trap VEGF Trap VEGF Fc portion

P P

P P

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Navigating Multiple Pathways: Targeted Therapies

VEGF Trap VEGF Trap VEGF Fc portion

P P

P P

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Navigating Multiple Pathways: Targeted Therapies

VEGF Trap VEGF Trap VEGF

P P

P P

BLOQUEO de la activación del VEGFR clinicaloptions.com/oncology

Navigating Multiple Pathways: Targeted Therapies

Inhibición de Tirosina Kinasa y VEGF VEGF TKI (Inhibidor de la Tirosina Kinasa)

P P

P P

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Navigating Multiple Pathways: Targeted Therapies

Tyrosine Kinase Inhibition and VEGF VEGF TKI

P P

P P

BLOQUEO de la cascada de Fosforilación clinicaloptions.com/oncology

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Toxicidad de clase de los Anti-VEGF  Hipertensión

 Incremento de los LFT

 Fatiga

 Dolor en el sitio del tumor

 Coágulos

 Proteinuria

 Sangrado (Epistaxis, hemoptisis, tumoral)

 Hipotiroidismo?

 Cefalea

 Perforación intestinal

 Eventos neurológicos

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Agentes con múltiples dianas – VEGF Plus

Navigating Multiple Pathways: Targeted Therapies

Sunitinib (SU11248): TKI contra múltiples receptores  Split Kinase Domain RTKs VEGFR-1 PDGFR-α VEGFR-2 PDGFR-β FLT4 CSF1R Fms KIT FLT3

IC50 (µM)[1] – VEGFR2:

4

– PDGFRβ:

39

– KIT:

1

– FLT3 (WT):

8

– EGFR:

>10,000



Efectivo contra VEGFR, PDGFR, KIT y FLT3 a concentraciones µM



Antagoniza receptores involucrados en la proliferación celular y angiogénesis



No tiene actividad contra otras RKTs (ie, EGFR); evaluado en > 40 otras RTKs y kinasas proteicas



Actividad en GIST, renal, mama, etc

Chow LQ, et al. J Clin Oncol. 2007;25:884-896.

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Sorafenib (BAY 43-9006): Un inhibidor de la transducción de señales Molécula Raf-1

IC50, µM ± SD 6±3

 Inhibe tanto la kinasa Raf y VEGFR

VEGFR-2

90 ± 15

VEGFR-3

20 ± 6

 Inhibe la proliferación tumoral y la angiogénesis

PDGFR-ß

57 ± 20

 Activo en varias neoplasias

C-kit

68 ± 21

Flt3

58 ± 20

EGFR

Inactivo a 10,000

Wilhelm SM, et al. Cancer Res. 2004;64:7099-7109.

 Especialmente: Carcinoma de células renales; Carcinoma hepatocelular

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Angiogenesis tumoral: Bevacizumab y TKIs con múltiples dianas Factores de crecimiento angiogénicos Pericito O2 Célula

Célula tumoral

Endotelial

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Célula Endotelial VEGF-B

VEGF-C

VEGF-A VEGF-R1 (Flt-1)

VEGF-R2 (KDR)

VEGF-D VEGF-R3 (Flt-4)

PROLIFERACION MIGRACION

MIGRACION

Ras

PI3K

Raf

Akt

MEK p38MAPK

Caspase-9

eNOS

ERK

CELL ACTIVATION / SURVIVAL ANGIOGENESIS VASCULOGENESIS

LINFANGIOGENESIS clinicaloptions.com/oncology

Navigating Multiple Pathways: Targeted Therapies

Bevacizumab VEGF-B

VEGF-C

VEGF-A VEGF-R1 (Flt-1)

VEGF-R2 (KDR)

VEGF-D VEGF-R3 (Flt-4)

PROLIFERATION MIGRATION

MIGRATION

Ras

PI3K

Raf

Akt

MEK p38MAPK

Caspase-9

eNOS

ERK

CELL ACTIVATION / SURVIVAL ANGIOGENESIS VASCULOGENESIS

LiNFANGIOGENESIS clinicaloptions.com/oncology

Navigating Multiple Pathways: Targeted Therapies

Bevacizumab VEGF-B

VEGF-C

VEGF-A VEGF-R1 (Flt-1)

PTK/ZK

VEGF-R2 (KDR)

VEGF-D VEGF-R3 (Flt-4)

Vandetanib Motesanib

Sunitinib

PROLIFERATION MIGRATION

MIGRATION

Sorafenib

Ras

PI3K

Raf

Akt

MEK p38MAPK

Caspase-9

eNOS

ERK

CELL ACTIVATION SURVIVAL ANGIOGENESIS VASCULOGENESIS

LYMPHANGIOGENESIS clinicaloptions.com/oncology

Navigating Multiple Pathways: Targeted Therapies

Angiogenesis tumoral: Bevacizumab y TKIs con múltiples dianas PDGF

Pericito

O2 Célula Endotelial

Célula tumoral

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Pericito PDGF-B PDGF-Rβ

Ras

PI3K

Raf

Akt

MEK p38MAPK

Caspase-9

eNOS

ERK CELL ACTIVATION VESSEL MATURATION

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Pericito PDGF-B PDGF-Rβ

Sorafenib

Vandetanib Sunitinib Motesanib

Ras

PI3K

Raf

Akt

PTK/ZK

MEK p38MAPK

Caspase-9

eNOS

ERK CELL ACTIVATION VESSEL MATURATION

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Navigating Multiple Pathways: Targeted Therapies

Angiogenesis tumoral: Bevacizumab y TKIs con múltiples dianas Pericite O2 Célula tumoral

Célula Endotelial Factores paracrinos

SOURCE: Angiogenesis Foundation

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Célula Tumoral KIT

RET

Flt-3

Múltiples Factores de Crecimiento

Src

Ras

Rac1

Raf

PI3K

JNK

MEK

Akt

p38MAPK

ERK

CELL PROLIFERATION SURVIVAL

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Navigating Multiple Pathways: Targeted Therapies

Célula Tumoral KIT

Sorafenib PTK/ZK

RET

Flt-3

Múltiples Factores de Crecimiento

Sunitinib Vandetanib

Motesanib

Src

Ras

Rac1

Raf

PI3K

JNK

MEK

Akt

p38MAPK

ERK

CELL PROLIFERATION SURVIVAL

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Navigating Multiple Pathways: Targeted Therapies

Angiogénesis tumoral: Células y Vías F. de crecimiento angiogénico

PDGF

Pericite

O2 Célula tumoral

Célula Endotelial

Factores Paracrinos

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Navigating Multiple Pathways: Targeted Therapies

Toxicidad de clase de los Anti-VEGF  Hipertensión

 Incremento de los LFT

 Fatiga

 Dolor en el sitio del tumor

 Coágulos

 Proteinuria

 Sangrado (Epistaxis, hemoptisis, tumoral)

 Hipotiroidismo?

 Cefalea  Eventos neurológicos

 Rash cutáneo  Mielosupresión  Náusea y vómito  Diarrea clinicaloptions.com/oncology

Navigating Multiple Pathways: Targeted Therapies

Reducción de la actividad de tirosina kinasas por TKI con multi-dianas Kinase Inhibition

Sunitinib (IC50, µM)[1,5]

Motesanib (IC50, µM)[2]

Sorafenib (IC50, µM)[3]

PTK/ZK (IC50, µM)[4]

Vandetanib (IC50, µM)[5]

Pazopanib (IC50, µM)[5,6]

VEGFR-1

2

2

-

77

1600

10

VEGFR-2

4#

3

90

37

40

30

VEGFR-3

17

6

20*

620

110

47

-

84

-

-

39#

-

57*

580

1100

84

Raf

-

91

6

3600[7]

-

-

c-Kit

1#

8

68

730

> 20,000

74

FLT3

8

-

58

-

EGFR

> 10,000

> 3000

> 10,000

> 10,000

500

-

224 [8]

59

47[9]

-

130[10]

-

PDGFR PDGFR-β

RET Assay

-

In vitro biochemical kinase assay, except where indicated as # (cellular assay)

*Murine-based protein used. 1. Mendel DB, et al. Clin Cancer Res. 2003;9:327-337. 2 Herbst et al. Presented at 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. Sept 28- Oct 1, 2004. 3 Wilhelm SM, et al. Cancer Res. 2004:64;7099-7109. 4 Wood JM, et al. Cancer Res. 2000;60:21782189. 5 Chow L and Eckhardt G, J Clin Oncol 2007;25:884-896. 6 Podar K, et al. Proc Natl Acad Sci USA 2006;103:19478-19483. 7 Hess-Stumpp H, et al. ChemBioChem 2005;6: 550–557. 8 Kim D, et al. J Clin Endocrinol Metab. 2006;91:4070-4076. 9 Carlomagno F. et al. J Natl Cancer Inst 2006;98:326 – 334. 10 Carlomagno F. et al. Cancer Res 2002;62:7284-7290. clinicaloptions.com/oncology

Antagonizando el EGFR

Navigating Multiple Pathways: Targeted Therapies

EGFR es una proteina transmembrana Dominio Extracelular

Dominio Transmembrana

Dominio intracelular

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Navigating Multiple Pathways: Targeted Therapies

La activación del EGFR activa múltiples procesos

Shc PI3-K

Grb2 Sos-1 Ras

AKT MEKK-1 mTOR

MKK-7

Raf MEK clinicaloptions.com/oncology ERK

Navigating Multiple Pathways: Targeted Therapies

La activación del EGFR activa múltiples procesos

Shc PI3-K

Grb2 Sos-1 Ras

AKT MEKK-1 mTOR

MKK-7

Raf MEK clinicaloptions.com/oncology ERK

Navigating Multiple Pathways: Targeted Therapies

La activación del EGFR activa múltiples procesos Shc PI3-K

Grb2 Sos-1 Ras

AKT MEKK-1 mTOR

MKK-7

Raf MEK ERK

JNK

Apoptosis Resistance

Proliferation

Angiogenesis

Metastasis

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Navigating Multiple Pathways: Targeted Therapies

Dimerización del EGFR por ligandos

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Dimerización del EGFR por ligandos I

II IV III

Ferguson KM. Biochem Soc Trans. 2004;32:742-745. Dawson JP, et al. Mol Cell Biol. 2005;25:7734-7742.

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Navigating Multiple Pathways: Targeted Therapies

Dimerización del EGFR por ligandos I

II

III

Ferguson KM. Biochem Soc Trans. 2004;32:742-745. Dawson JP, et al. Mol Cell Biol. 2005;25:7734-7742.

IV

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Dimerización del EGFR por ligandos I

II

III

Ferguson KM. Biochem Soc Trans. 2004;32:742-745. Dawson JP, et al. Mol Cell Biol. 2005;25:7734-7742.

IV

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Dimerización del EGFR por ligandos I

II

III

Ferguson KM. Biochem Soc Trans. 2004;32:742-745. Dawson JP, et al. Mol Cell Biol. 2005;25:7734-7742.

IV

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Dimerización del EGFR por ligandos I

II

III IV

Ferguson KM. Biochem Soc Trans. 2004;32:742-745. Dawson JP, et al. Mol Cell Biol. 2005;25:7734-7742.

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Navigating Multiple Pathways: Targeted Therapies

Dimerización del EGFR por ligandos I

II

III IV

Ferguson KM. Biochem Soc Trans. 2004;32:742-745. Dawson JP, et al. Mol Cell Biol. 2005;25:7734-7742.

clinicaloptions.com/oncology

Navigating Multiple Pathways: Targeted Therapies

Dimerización del EGFR por ligandos I

II

III IV

Ferguson KM. Biochem Soc Trans. 2004;32:742-745. Dawson JP, et al. Mol Cell Biol. 2005;25:7734-7742.

(D279 H280)

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Dimerización del EGFR por ligandos

Shc PI3-K

Grb2 Sos-1 Ras

AKT

Ferguson KM. Biochem Soc Trans. 2004;32:742-745. Dawson JP, et al. Mol Cell Biol. 2005;25:7734-7742.

MEKK-1

Raf clinicaloptions.com/oncology

Navigating Multiple Pathways: Targeted Therapies

Cómo explotar el EGFR en oncología  Pequeñas Moléculas – Erlotinib, gefitinib

 Anticuerpos monoclonales – Cetuximab – Panitumumab

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EGFR TKI Extracellular

Intracellular

Shc PI3-K

Grb2 Sos-1 Ras

AKT MEKK-1

Raf clinicaloptions.com/oncology

MEK

Navigating Multiple Pathways: Targeted Therapies

MOAs Anti-EGFR Extracelular

Intracelular Shc PI3-K

Grb2 Sos-1 Ras

AKT MEKK-1

Raf clinicaloptions.com/oncology

Navigating Multiple Pathways: Targeted Therapies

MOAs Anti-EGFR (cont’d) L1

CR1

L1

CR1

EGF L2

EGF L2

EGF, TGF-α

Bloqueo a la unión de ligando

L1

X

L1 CR1

CR1 L2

L2

Bloqueo del ligando

CR2 CR2

Johns TG, et al. J Biol Chem. 2004;279:30375-30384.

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Hybridoma Technology: Evolution Mouse

Chimeric

Humanized

Fully Human

100% mouse protein

34% mouse protein

10% mouse protein

100% human protein

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Navigating Multiple Pathways: Targeted Therapies

ADCC

Célula tumoral

Anticuerpo

Killer cell, NK, macrófage, neutrófilo clinicaloptions.com/oncology

Navigating Multiple Pathways: Targeted Therapies

Anti EGFR en cáncer  Pequeñas Moléculas (TKI) – Erlotinib – Carcinoma de células no pequeñas (NSCLC) en 2nda y 3ra línea – Carcinoma de páncreas (Junto con Gemcitabina) en 1ra línea

– Cetuximab – Carcinoma de colon y recto metastásico (en varias líneas)ç – Carcinoma de cabeza y cuello

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Cuál diana? Shc PI3-K

Grb2 Sos-1 Ras

AKT MEKK-1 mTOR

MKK-7

Raf MEK ERK

JNK

Apoptosis

Proliferation

Angiogenesis

Metastasis

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Navigating Multiple Pathways: Targeted Therapies

Cuál diana? Shc PI3-K

Grb2 Sos-1 Ras

AKT MEKK-1 mTOR

MKK-7

Raf MEK ERK

JNK

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Navigating Multiple Pathways: Targeted Therapies

Sos-1 PI3-K Grb2

Shc

MEK

Ras

Raf MEKK-1

JNK MKK-7 ERK AKT

Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer Center.

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Dónde está la diana? Sos-1 PI3-K Grb2

Shc

MEK

Ras

Raf MEKK-1

JNK MKK-7 ERK AKT

Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer Center.

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EGF

Perspectiva del Ingeniero EGFR

EGFR

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