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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. Strategies to inhibit VEGF signalling.

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APPLICAZIONI CLINICHE DEI FARMACI ANTIANGIOGENETICI

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  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 • 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

  5. 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

  6. 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$

  7. 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

  8. 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)

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

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

  11. 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

  12. Binding del VEGF ai recettori VEGFR-3/Flt-4 VEGFR-1/Flt-1 VEGFR-2/KDR 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. Agents affecting all VEGFRs • AZD2171 • LY317615 (Enzastaurin) • CEP7055 • GW786024

  15. 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

  16. 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

  17. Combination of 2 selective inhibitors approach

  18. Combined blockade of EGFR and VEGF Erlotinib Cetuximab, etc Bevacizumab etc. EGFR Endothelial cells Cancer cells VEGF Angiogenesis Cell Proliferation Tortora et al. 2004

  19. 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.)

  20. Indirect Comparison of the Efficacy Results in BOND-1 and BOND-2 Modified from Saltz et al., ASCO 2005

  21. Multitargeted agents approach

  22. 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)

  23. 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

  24. 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

  25. 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)

  26. 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

  27. SU11248 is active in different tumors • Activity observed in leukemia • Active in sarcomas • Active in GIST (including those resistant to imatinib)

  28. 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.

  29. 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

  30. 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

  31. 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

  32. 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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