Cancer targeted therapy José Carlos Machado

Cancer progression

Acquired propeties

Incidence and age

OncogenesTumour supressor genes Cancer is a genetic disease!

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

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

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

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

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

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

JC Becker et al.

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

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: , 2005

Tsao et al, NEJM 2005; 353: Erlotinib – effect on overall survival

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

Response to gefitinib treatment

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

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

Abordagem simplista

Abordagem integrada

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.