La presentazione è in caricamento. Aspetta per favore

La presentazione è in caricamento. Aspetta per favore

APPLICAZIONI CLINICHE DEI FARMACI ANTIANGIOGENETICI Giampaolo Tortora Cattedra di Oncologia Medica UOC e Laboratori di Terapia molecolare dei tumori Dipartimento.

Presentazioni simili


Presentazione sul tema: "APPLICAZIONI CLINICHE DEI FARMACI ANTIANGIOGENETICI Giampaolo Tortora Cattedra di Oncologia Medica UOC e Laboratori di Terapia molecolare dei tumori Dipartimento."— Transcript della presentazione:

1 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

2 Strategies to inhibit VEGF signalling Ferrara & Kerbel Nature 438: 967–974, 2005.

3 VEGF and VEGFR inhibitors under investigation Hicklin and Ellis, JCO 2005

4 Bevacizumab VEGF isoforms recognised by hypervariable murine antibody fragment Human IgG-1 93% human, 7% murine Recognizes all isoforms of VEGF ( Kd = 8x10 –10 M) 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)

5 Conseguenze della iperespressione e ipersecrezione di VEGF Migrazione e proliferazione endoteliale Distorsione dellarchitettura vascolare Aumento della permeabilità vascolare e della PIF Modulazione della risposta immune

6 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$ NormalizzataNormale Anormale Bevacizumab Bevacizumab: effetti sulla vascolarizzazione tumorale

7 Willett CG, et al. Nat Med 2004;10:145–7 Evidenza diretta degli effetti di Bevacizumab sulla vascolatura tumorale umana: studio fase I Avastin 5 mg/kg Avastin 5 mg/kg + 5-FU i.c. + Radioterapia Patienti con ca rettale primario e non metastatico (n=6) Chirurgia 2 settimane 3 volte ogni 2 settimane Sangue/urine TAC funzionale/PET Endoscopia Biopsia tumorale 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)

8 Ca colorettale 1a linea (NEJM 2004)Ca colorettale 2a linea (ASCO 2005) Ca polmonare 1a linea (ASCO 2005)Ca mammario 1a linea (ASCO 2005) Avastin aumenta la sopravvivenza in diversi tumori

9 Giantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2) E3200: progression-free survival 50% Incremento netto

10 Giantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2) E3200: overall survival

11 > Planned trials in adjuvant colon cancer

12 Binding del VEGF ai recettori VEGFR-1/Flt-1 VEGFR-2/KDR VEGFR-3/Flt-4 LYMPHANGIOGENESIS ANGIOGENESIS

13 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

14 AZD2171 LY (Enzastaurin) CEP7055 GW Agents affecting all VEGFRs

15 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 AZD2171 VEGFR3 (Flt-4) VEGFR1 (Flt-1) VEGFR2 (KDR)

16 Receptor VEGF DAGIP3/Ca 2+ PKC- COX2 mRNA Tumor invasion Angiogenesis ENZASTAURIN Activation GSK3 AKT Caspase 9 Apoptosis Protein translation IL-6 IL-8 PKC- and the Proposed Action of Enzastaurin on Angiogenesis and Apoptosis Acyclic indolylmaleimide competing with the ATP binding site

17 Combination of 2 selective inhibitors approach

18 EGFR VEGF Endothelial cells Cancer cells Angiogenesis Cell Proliferation Tortora et al Erlotinib Cetuximab, etc Bevacizumab etc. Combined blockade of EGFR and VEGF

19 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). 3 Phase II studies of Bevacizumab and Erlotinib in Patients with Renal Carcinoma (RCC), Breast cancer and NSCLC 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.)

20 Indirect Comparison of the Efficacy Results in BOND-1 and BOND-2 BOND-1 C225 BOND-2 C225 + BEV BOND-1 C225 + CPT BOND-2 C225 + CPT + BEV No. patients Prev oxal (%) RR (%) TTP (months) Median OS (months) Modified from Saltz et al., ASCO 2005

21 Multitargeted agents approach

22 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) Multitargeted agents affecting VEGF-Rs and EGFR, PDGF-Rs etc.

23 EGFR VEGF Endothelial cells Cancer cells TGF KDR Angiogenesis Cell Proliferation ZD6474 Tortora & Ciardiello 2003 Carlomagno et al, Cancer Res Ciardiello et al., Clin Cancer Res Ciardiello et al., Clin Cancer Res Damiano et al., Clin Cancer Res 2005 ZD6474 inhibits KDR and EGFR RET

24 Progression-free survival (days) Probability of remaining progression-free Median progression-free survival: Placebo + docetaxel = 12.0 weeks ZD mg + docetaxel = 18.7 weeks ZD mg + docetaxel = 17.0 weeks DATI ANCORA IMMATURI PER OS Objective responses Placebo+D = 12% ZD 100 +D = 26% ZD 300 +D = 18% Randomized Phase II trial of ZD6474 plus docetaxel in patients with NSCLC. Primary endpoint : PFS

25 Targeting VEGF and EGFR: AEE788 Phase 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 2 Baselga J, et al. J Clin Oncol 2005;23(June 1 Suppl.):198s (Abstract 3028) 3 Martinelli E, et al. J Clin Oncol 2005;23(June 1 Suppl.):201s (Abstract 3039)

26 The endothelial cell-pericyte network of signals Nature Review Cancer Pericytes protect endothelial cells from apoptosis and overexpress PDGF-R PDGF-R is overexpressed in many tumors PDGF-R and VEGF cooperate

27

28 SU11248 is active in different tumors - Activity observed in leukemia - Active in sarcomas - Active in GIST (including those resistant to imatinib)

29 *Escudier et al. J Clin Oncol. 1999;17: ; Yang et al. N Engl J Med. 2003;349: ; Motzer et al. J Clin Oncol. 2004; 22: No.ORR, %TTP, mo SU Interleukin-2* 65 5NA Interferon- * 48 2NA Avastin (high dose) Placebo Multiple agents in phase II trials SU11248 in mRCC Activity Versus Other Second-Line Agents

30 Phase II study of SU11248 in MBC Miller et al., ASCO 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.

31 Complete inhibitor of the VEGF receptor tyrosine kinases VEGFR1(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 PTK787/ZK (Vatalanib) Formula: C 24 H 21 N 4 Cl MW = PTK787/ZK (Vatalanib) Formula: C 24 H 21 N 4 Cl MW = PTK/ZK: A multi-VEGF receptor tyrosine kinase inhibitor

32 ONGOING AND PLANNED PHASE IIICONFIRM STUDIES Over 700 pts treated up to date in combination with CT Chemonaive CRC FOLFOX + PTK CPT-11/FU resistant CRC FOLFOX + PTK

33 BAY (Sorafenib) Bisaryl urea, multiple targeted inhibitor. Inhibits B-Raf-1 kinase (including the mutated form) with IC 50 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. Cl F 3 CNHNH O O N NH CH 3 O


Scaricare ppt "APPLICAZIONI CLINICHE DEI FARMACI ANTIANGIOGENETICI Giampaolo Tortora Cattedra di Oncologia Medica UOC e Laboratori di Terapia molecolare dei tumori Dipartimento."

Presentazioni simili


Annunci Google