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Download Cancer targeted therapy José Carlos Machado Cancer progression
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Cancer targeted therapy José Carlos Machado Cancer progression Acquired propeties Incidence and age Cancer is a genetic disease! Oncogenes Tumour supressor genes 5-fluorouracil + leucoverin in CCRm Efeito 5-FU + LV Control P value RR 21% 11% <0.0001 OS 11.7 m 10.5 m 0.004 Thirion P, et al. J Clin Oncol 2004;22:3766 Buyse M, et al. Lancet 2000;356:373. Irinotecan in CCRm Efeito Irinotecan Control P value RR 49% 31% <0.001 PFS 6.7 m 4.4 m <0.001 OS 17.4 m 14.1 m 0.031 Douillard JY, et al. Lancet 2000;355:1041 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. EGFR Function in Normal Cell ATP TK TK ATP + Gene Transcription Cell Cycle Progression Antiapoptosis Cell Proliferation Angiogenesis EGFR tyrosine kinase inhibitors ATP Anti-EGFR mAbs TK - Anti-ligand mAbs TK TK - - Bispecific Abs TK - Immune effector cell Strategies to inhibit EGFR signaling 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 TY Lynch et al. N Engl J Med. 350:2129-2139, 2005 Antes Depois 28% no Japão e 10% no Europa Ausência de beneficio quando comparado com quimioterapia convencional Erlotinib – effect on overall survival Tsao et al, NEJM 2005; 353:133-132 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 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 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 Riely et al. Clinical Cancer Research 12, 7232 (December 2006) Abordagem simplista Abordagem integrada Conclusions • Targeted therapies have been producing promising results, namely in specific subgroups 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.
