1. Cancer targeted therapy José Carlos Machado

2. Cancer progression

3. Acquired propeties

4. Incidence and age

5. OncogenesTumour supressor genes Cancer is a genetic disease!

6. 5-fluorouracil + leucoverin in CCRm Efeito5-FU + LVControlP value RR21%11%<0.0001 OS11.7 m10.5 m0.004 Thirion P, et al. J Clin Oncol 2004;22:3766 Buyse M, et al. Lancet 2000;356:373.

7. Irinotecan in CCRm Douillard JY, et al. Lancet 2000;355:1041 EfeitoIrinotecanControlP value RR49%31%<0.001 PFS6.7 m4.4 m<0.001 OS17.4 m14.1 m0.031

8. CRC carcinogenesis Fodde R, et al. Nature Rev Cancer 2001;1:55–67

9. EGFR expression in CRC 70-75% of CRC display EGFR overexpression Increased signalling Goldstein NS and Armin M. Cancer 2001;92: 1331.

10. TK EGFR Function in Normal Cell TK ATP Cell Proliferation Antiapoptosis Angiogenesis Gene Transcription Cell Cycle Progression +

11. TK Strategies to inhibit EGFR signaling - - - - EGFR tyrosine kinase inhibitors Anti-EGFR mAbs Anti-ligand mAbs Bispecific Abs Immune effector cell ATP

12. JC Becker et al.

13. 30 Yrs’ Research: Effect of Standard Chemotherapy in Metastatic NSCLC has Reached a Plateau Response rate – 19% Median TTP – 3.7 mos Median OS – 8 mos Schiller et al ‘02

14. Gefitinib and lung cancer AntesDepois 28% no Japão e 10% no Europa Ausência de beneficio quando comparado com quimioterapia convencional TY Lynch et al. N Engl J Med. 350:2129-2139, 2005

15. Tsao et al, NEJM 2005; 353:133-132 Erlotinib – effect on overall survival

16. Response to therapy with TKIs depends on EGFR mutation status TY Lynch et al. N Engl J Med. 350:2129-2139, 2005 JG Paez et al. Science. 304:1497-1500, 2005

17. Response to gefitinib treatment

18. EGFR mutations and response to treatment with erlotinib or gefitinib – retrospective studies Riely et al. Clinical Cancer Research 12, 7232 (December 2006)

19. EGFR mutations and response to treatment with erlotinib or gefitinib – prospective studies Riely et al. Clinical Cancer Research 12, 7232 (December 2006) Collectively, these studies show a 75% response rate for patients whose tumors have mutations compared with a response rate of <10% for those with wild-type EGFR

20. Abordagem simplista

21. Abordagem integrada

22. Conclusions Targeted therapies have been producing promising results, namely in specific sub- groups of cancer patients Research on the molecular aetiology of cancer is finally paying off! Don’t stop now! Health-care institutions have the chance to save significant resources by targeting these therapies.