Francesco Scaglione, MD, PhD Department of Medical Biotechnology and Translational Medicine

1. Target Therapy in oncology Francesco Scaglione, MD, PhD Department of Medical Biotechnology and Translational Medicine Postgradute School of clinical pharmacology University of Milan Clinical Pharmacology Unit Niguarda Ca’ Granda- Hospital Milan,Italy

2. Sviluppo storico della chemioterapia antineoplastica 1945 Mecloretamina 1950 Metotrexato 6-Mercaptopurina Busulfan 1955 Clorambucil Ciclofosfamide 1960 Vinblastina, vincristina Fluorouracile, actinomicina D Melfalan 1965 • Prima chemioterapia adiuvante con actinomicina D nel tumore di Wilms Procarbazina, 6-tioguanina Citosina arabinoside Adriamicina 1970 Bleomicina, dacarbazina da G. Bonadonna, 1999 (modificata)

3. Sviluppo storico della chemioterapia antineoplastica (II) 1975 • CMF adiuvante nel ca. mammario • Terapia adiuvante nell’osteosarcoma • Trapianto di midollo osseo • PVB nei tumori del testicolo CCNU, BCNU, cisplatino 1980 • Inizio chemioterapia primaria in vari tumori solidi resecabili Etoposide, mitoxantrone 1985 • Trapianto autologo con GM-CSF • Espansione chemioterapia primaria Carboplatino Ifofosfamide + MESNA 1990 Paclitaxel, docetaxel Topotecan, irinotecan Gemcitabina Oxaliplatino • Terapia antiemetica 1995 Target therapy 2000 da G. Bonadonna, 1999 (modificata)

4. Changing of the Guard A Paradigm Shift in the Treatment of Cancer • Conventional cytotoxic drugs interact with DNA to prevent cell replication but are not specific to cancer cells • We are moving to targeted therapies which specifically target cancer cells

6. Signalling Pathways Identificare mutazioni tipiche della cellula neoplastica

7. Target therapy: • Identificazione del bersaglio • Sopravvivenza e crescita delle cellula tumorale dipendono dal bersaglio

8. …. la comparsa degli “inib” e degli “umab” ...

9. Targeted Therapies • Monoclonal antibodies: proteine che si legano a recettore o altra molecola di segnale extracellulare • Tyrosine Kinase Inhibitors: molecola che lega e inibisce attività enzimatiche intracellulari • Gli “umab • Gli “inib”

10. umab umab I I I I I I Dalla biologia alla biotecnologia ai nuovi farmaci Second messanger ……….inib Transcription Translation Proteolysis From JB Gibbs, 2000, modified

11. Farmaci a Bersaglio Molecolare

13. Kinome VEGF-R PDGF-R • 518 protein kinases • Tyrosine kinase group 30 families : • > VEGFR • > PDGFR • > FGFR • > EGFR RAF Cell signaling technology

14. Whatis a tyrosine kinase receptor ?

15. Molecular mechanism of action of TKI Coloured molecule: ATP Gray molecule: inhibitor

16. Carcinoma Renale Here Lies Interferon Killed by Sunitinib & Sorafenib

17. Sorafenib

18. Kinase inhibited by Sorafenib Sorafenib 22

19. Sorafenib scheme of action

20. TARGET study: results www.nexavar-international.com

21. TARGET study: results • Cross-over: 48% of patient under placebo switched to Sorafenib www.nexavar-international.com

22. Tumorresponse rate Overall Response 84%

23. Adverse effects of Sorafenib ESCUDIER B, Sorafenib for Treatment of Renal Cell Carcinoma: Final Efficacy and Safety Results of the Phase III Treatment Approaches in Renal Cancer Global Evaluation Trial, 2009 Bernard Escudier, et al

24. Sunitinib

25. Kinase inhibited by Sunitinib Sorafenib Sunitinib 29

26. Clinical trial results Sutent average PFS is 11,8 months, compared with 5,5 months for patients receiving interferon alfa. Overall Survival and Updated Results for Sunitinib Compared With Interferon Alfa in Patients With Metastatic Renal Cell Carcinoma Robert J. Motzer et al.

27. Clinical trial results: Tumorresponse

28. Clinical trial results: Adverse effects

29. Conclusion on sunitinib • More efficient than Ifn-a. • Came as first line because of comparison with interferon • Best in class • More high grade side effects • Requires treatment holiday BUT

30. Understanding the use of targetedtherapies in RCC Robert J. Amato, Targeted Therapy and Renal Cell Carcinoma:  Are We Making Progress? 2007

31. Pazopanib

32. Kinase profile of Pazopanib Sorafenib Sunitinib Pazopanib 36

33. Scheme of action, Pazopanib VEGF-A/B PDGF-a/b VEGF-C VEGFR-1/2 PDGFR Pz VEGFR-3 Pz Pz Pz Pz Pz Pz

34. Clinical trial of Pazopanib Pazopanib : 9,2 months Placebo : 4,2 months Cora N. Sternberg A randomized, double-blind phase III study of pazopanib in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma, 2009

35. Clinical trial of Pazopanib

36. Conclusion on clinical trial Pazopanib is efficacy SO is pazopanib a real progress in RCC treatment ?

37. Lookingat Adverse effects…

38. New coming indication • Lots of on-going studies for theses TKIs in RCC indication • Sorafenib vs interferon • ASSURE Sorafenib or Sunitinib as adjuvant • COMPARZ study ( Ph III ) Pazopanib vs Sunitinib 875 patients enrolled with advanced/metastatic RCC datas expected during 2010 Provide a direct compararison of the efficacity, safety and tolerability for Sunitinib and Pazopanib

40. Targeted Cancer Therapy „The dream of the Magic Bullet“ Side Effect-Free Cure of Cancer

41. Paul Ehrlich 1854 - 1915 • Father of Chemotherapy • Salvarsan for Treatment of Syphilis • Nobel Prize 1908 • “Magic Bullet Concept”

42. Kit Receptor Phenotype ADP + P ATP Proliferation Survival Adhesion Invasion Metastasis Angiogenesis

43. Kit Receptor Phenotype ATP Imatinib Proliferation Survival Adhesion Invasion Metastasis Angiogenesis = imanitib contact point

44. EORTC study: Imatinib for Advanced GISTSurvival Benefit Verweij, et al 2004

45. c-Kit Receptor Structure Extracellular Domain (exon 9, 10.2%) Juxtamembrane Domain (exon 11, 66.1%) ATP Tyrosine Kinase Domain I (exon 13/14, 1.2%) Tyrosine Kinase Domain II (exon 17, 0.6%) = common mutation site

46. Overall Survival by Genotype Exon 11 Exon 11 Exon 9 No Mutation

47. Signalling Pathways Il cancro evolve Mutazioni appaiono in corso di terapia Cercare mutazioni Sviluppare farmaci multi-target !!!

48. Target therapy”? ….quale bersaglio? Grazie per l’attenzione !

49. Grazie per l’attenzione