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APPLICAZIONI CLINICHE DEI FARMACI ANTIANGIOGENETICI. Giampaolo Tortora. Cattedra di Oncologia Medica UOC e Laboratori di Terapia molecolare dei tumori Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica Università di Napoli Federico II. Strategies to inhibit VEGF signalling.

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applicazioni cliniche dei farmaci antiangiogenetici

APPLICAZIONI CLINICHE DEI FARMACI ANTIANGIOGENETICI

Giampaolo Tortora

Cattedra di Oncologia Medica

UOC e Laboratori di Terapia molecolare dei tumori

Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica

Università di Napoli Federico II

slide2

Strategies to inhibit VEGF signalling

Ferrara & Kerbel Nature 438: 967–974, 2005.

bevacizumab
Bevacizumab
  • 93% human, 7% murine
  • Recognizes all isoforms of VEGF (Kd = 8x10–10M)
  • Terminal half-life 17–21 days
  • No DLT as single agent
  • inhibits all functions of the VEGF ligand:
    • on vascular endothelial cells
    • on non-endothelial cells (dendritic cells, monocytes)

VEGF isoforms recognised by hypervariable murine antibody fragment

Human IgG-1

conseguenze della iperespressione e ipersecrezione di vegf
Conseguenze della iperespressione e ipersecrezione di VEGF
  • Migrazione e proliferazione endoteliale
  • Distorsione dell’architettura vascolare
  • Aumento della permeabilità vascolare e della PIF
  • Modulazione della risposta immune
slide6

Bevacizumab: effetti sulla vascolarizzazione tumorale

Bevacizumab

Normale

Normalizzata

Anormale

Riduce

la pressione del liquido interstiziale

e la densità microvascolare

Incrementa

il rilascio intratumorale dei farmaci

Modificato da Jain RK. Nat Med 2001; 7:987–9

Willett CG. et al. Nat Med 2004; 10:145–7

Tong R. et al. Cancer Res 2004; 64:3731–6$

slide7

Evidenza diretta degli effetti di Bevacizumab sulla vascolatura tumorale umana: studio fase I

Patienti con ca rettale primario e non metastatico

(n=6)

Avastin 5 mg/kg +5-FU i.c. + Radioterapia

Avastin 5 mg/kg

Chirurgia

2 settimane

3 volte ogni 2 settimane

  •  perfusione sanguigna tumorale(40–44%, p<0.05)
  •  volume sanguigno tumorale(16–39%, p<0.05)
  •  densità microvascolare(25–59%, p<0.05)

 pressione interstiziale

(da 15.0 ± 2.0 a 4.0 ± 2.2 mm Hg, p<0.01)

Sangue/urine TAC funzionale/PET Endoscopia Biopsia tumorale

Willett CG, et al. Nat Med 2004;10:145–7

slide8

Avastin aumenta la sopravvivenza in diversi tumori

Ca colorettale 1a linea (NEJM 2004)

Ca colorettale 2a linea (ASCO 2005)

Ca polmonare 1a linea (ASCO 2005)

Ca mammario 1a linea (ASCO 2005)

e3200 progression free survival
E3200: progression-free survival

50% Incremento netto

Giantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2)

e3200 overall survival
E3200: overall survival

Giantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2)

planned trials in adjuvant colon cancer

Studio

n

Tumore

Stadio

Trattamento

3450

Colon

BO17920

II (alto

FOLFOX4

vs

(Avant)

rischio) III

FOLFOX4 + Avastin

vs

XELOX + Avastin

NSABP C

-

08

2700

Colon

FOLFOX6 ± Avastin

II (alto

rischio) III

II (alto

E5205

3125

Colon

FOLFOX6 ± Avastin

rischio

QUAS

AR

-

2

1900

Colon

III

Xeloda ± Avastin

Planned trials in adjuvant colon cancer

>11.000

binding del vegf ai recettori
Binding del VEGF ai recettori

VEGFR-3/Flt-4

VEGFR-1/Flt-1

VEGFR-2/KDR

LYMPHANGIOGENESIS

ANGIOGENESIS

slide13
EGFR

gefitinib (IRESSA™)

erlotinib (Tarceva™)

ZD6474

AEE788

VEGFR

ZD6474

vatalanib

AZD2171

SU11248

AEE788

sorafenib

Bcr-Abl

imatinib (Glivec™)

c-Kit

AZD2171

imatinib

SU11248

PDGFR

imatinib

SU11248

sorafenib

Key receptor tyrosine kinases and selective inhibitors

slide14

Agents affecting all VEGFRs

  • AZD2171
  • LY317615 (Enzastaurin)
  • CEP7055
  • GW786024
azd2171

AZD2171

VEGFR2 (KDR)

VEGFR1

(Flt-1)

VEGFR3

(Flt-4)

AZD2171
  • AZD2171 is an oral therapy with potential application in multiple tumor types
  • AZD2171 has activity against VEGF receptors 1, 2 & 3- No activity on EGFR
  • Phase I clinical studies in refractory solid tumors underway
  • Manageable toxicity in early phase I
slide16

GSK3b

COX2

IP3/Ca2+

DAG

IL-8

AKT

IL-6

PKC-b and the Proposed Action of Enzastaurin on Angiogenesis and Apoptosis

Acyclic indolylmaleimide competing with the ATP binding site

VEGF

ENZASTAURIN

Receptor

  • Tumor invasion
  • Angiogenesis

Apoptosis

PKC-b

Caspase 9

Protein translation

Activation

mRNA

slide18

Combined blockade of EGFR and VEGF

Erlotinib

Cetuximab, etc

Bevacizumab etc.

EGFR

Endothelial cells

Cancer cells

VEGF

Angiogenesis

Cell Proliferation

Tortora et al. 2004

slide19

3 Phase II studies of Bevacizumab and Erlotinib in Patients with Renal Carcinoma (RCC), Breast cancer and NSCLC

  • RCC (59 pts.): 47% Responses (including MR) and 39% SD;

76% 1 year Overall survival (Hainsworth et al., ASCO 2004; Spigel et al., ASCO 2005).

  • NSCLC: 85% Disease control (including 20% PR);

52% 1 year Overall survival and 7 mo. PFS (Sandler et al., ASCO 2005).

  • Breast Cancer: 33% Disease control (including PR) in heavily pretreated patients. Early data (Rugo et al., ASCO 2005).

Hainsworth JD, et al. J Clin Oncol 2004;22(July 15 Suppl.): Abstract 4502

Sandler AB, et al. J Clin Oncol 2004;22(July 15 Suppl.) Abstract 2000

Rugo H et al., J Clin Oncol 2004;22(July 15 Suppl.)

slide20

Indirect Comparison of the Efficacy Results

in BOND-1 and BOND-2

Modified from Saltz et al., ASCO 2005

slide22

Multitargeted agents affecting

VEGF-Rs and EGFR, PDGF-Rs etc.

  • ZD6474 (VEGF-R2 + EGFR + RET)
  • AE778 (VEGF-R2 + EGFR)
  • SU11248 (VEGFRs + PDGF-Rs+ c-Kit)
  • Sorafenib (VEGFRs + PDGF-Rs + MAPK + Erk + c-Kit)
  • PTK787 (VEGFRs + PDGF-Rs)
slide23

ZD6474 inhibits KDR and EGFR

TGF

ZD6474

EGFR

KDR

Endothelial cells

RET

Cancer cells

VEGF

Angiogenesis

Tortora & Ciardiello 2003

Carlomagno et al, Cancer Res. 2002

Ciardiello et al., Clin Cancer Res. 2003

Ciardiello et al., Clin Cancer Res. 2005

Damiano et al., Clin Cancer Res 2005

Cell Proliferation

slide24

1.00

Median progression-free survival:

Placebo + docetaxel = 12.0 weeks

ZD6474 100 mg + docetaxel = 18.7 weeks

ZD6474 300 mg + docetaxel = 17.0 weeks

0.75

Probability of remaining progression-free

0.50

0.25

0

0

50

100

150

200

250

300

350

400

Progression-free survival (days)

Randomized Phase II trial of ZD6474 plus docetaxel in patients with NSCLC. Primary endpoint : PFS

Objective responses

Placebo+D = 12%

ZD 100 +D = 26%

ZD 300 +D = 18%

DATI ANCORA IMMATURI PER OS

targeting vegf and egfr aee788 phase i trial
Targeting VEGF and EGFR: AEE788Phase I trial
  • dose-dependent inhibition of EGFR signalling in skin and tumour observed
  • most common adverse events were diarrhea (67%), fatigue/asthenia (51%), anorexia (49%), rash (43%), nausea (42%) and vomiting (28%)
  • DLT (diarrhea) dose levels defined at 500 and 550 mg

2Baselga J, et al. J Clin Oncol 2005;23(June 1 Suppl.):198s (Abstract 3028)

3Martinelli E, et al. J Clin Oncol 2005;23(June 1 Suppl.):201s (Abstract 3039)

slide26

The endothelial cell-pericyte network of signals

  • Pericytes protect endothelial cells from apoptosis
  • and overexpress PDGF-R
  • PDGF-R is overexpressed in many tumors
  • PDGF-R and VEGF cooperate

Nature Review Cancer

slide28

SU11248 is active in different tumors

  • Activity observed in leukemia
  • Active in sarcomas
  • Active in GIST (including those resistant to imatinib)
slide29

SU11248 in mRCCActivity Versus Other Second-Line Agents

*Escudier et al. J Clin Oncol. 1999;17:2039-2043; †Yang et al. N Engl J Med. 2003;349:427-434;‡Motzer et al. J Clin Oncol. 2004; 22:454-463.

slide30

Phase II study of SU11248 in MBC

  • 6 weeks cycle (50 mg/day for 28 d. and 2 weeks rest).
  • 64 pts enrolled (80% HER-2 negative/unknown). The majority with multiple visceral sites. Heavily pretreated (several previous CT regimens, also in adjuvant setting).
  • Asthenia and diarrhea major grade 2 toxicities. 40% grade 3 neutropenia.
  • 51 evaluable for responses. PR: 7 (14%); SD > 6 mo: 1 (2%). Study is ongoing.
  • No obvious correlation between response and ER or HER-2 status.

Miller et al., ASCO 2005

slide31

PTK/ZK: A multi-VEGF receptor tyrosine kinase inhibitor

PTK787/ZK 222584

(Vatalanib)

Formula: C24H21N4Cl

MW = 346.82

  • Complete inhibitor of the VEGF receptor tyrosine kinasesVEGFR1(FLT-1), VEGFR2 (KDR) and VEGFR3 (FLT-4). It also inhibits PDGF-R.
  • Well tolerated up to 1250 mg/day (phase III dose, used up to 15 mo)
  • Rapidly absorbed (1 to 2.5 hours), T1/2: 3-6 hrs
  • Renal metabolism
slide32

ONGOING AND PLANNED PHASE IIICONFIRM STUDIES

Chemonaive CRC

FOLFOX + PTK

Over 700 pts treated up to date

in combination with CT

CPT-11/FU resistant CRC

FOLFOX + PTK

bay 43 9006 sorafenib

Cl

O

O

N

F

C

N

H

N

H

3

C

H

3

O

N

H

BAY 43-9006 (Sorafenib)
  • Bisaryl urea, multiple targeted inhibitor.
  • Inhibits B-Raf-1 kinase (including the mutated form) with IC50 of 6 nM, MAPK, ERK.
  • Inhibits also endothelial cells and VEGFR2, VEGFR-3,FLT-3, PDGFR, c-Kit.
  • Raf is probably important in endothelial cells and double targeting (Raf and VEGFR-2) may be critical.
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