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De la farmacogenética a la farmacogenómica Javier Benitez Programa Genética del Cáncer Humano Centro Nacional Investigaciones Oncológicas Madrid Junio 06 Antitumoral treatments -They are agressives, inspecifics and with a limited therapeutic margin. - Risk of toxicity , treatment failure or even death - Wide interpatient variability in effects Antitumoral treatments II -Children with ALL. 75% get total remision (cure) 25% with treatment failure and/or severe toxicity -Sarcomas: 50-75% long term survival (cure) Cases with severe toxicity CNS and GUS - Breat cancer: Tamoxifen for ER and PR positive tumors (50%) Secondary effects in some patients: Uterine cancer, tromboembolims Genetic bases of farmacological response - Genetic variability might explain many of these situations. -Their study could lead to individualised treatment and new drug developments. -Pharmacogenetics: It studies candidate genes -Pharmacogenomics: It describes a broader strategy to identify many genes that are relevant to the pharmacological effects of a given medication. It is based in a targeted (candidate pathways) or whole genome analysis. Enzimatic activity of TPMT-6MP according to genotype Cheok et al, Nat Review 2006 Correlation between TPMT genotype and 6MP toxicity Cheok et al, Nat Review 2006 Allelic frequencies in Spanish Population (www.bioinfo.cnio.es) Gene CYP11B1 CYP11B1 CYP11B2 CYP11B2 CYP17A1 CYP17A1 CYP1A1 CYP1A1 CYP2A7 CYP2A7 CYP2A7 CYP2A7 CYP2A7 CYP2A7 CYP2A7 CYP2A7 CYP2A7 CYP2A7 CYP2A7 CYP2A7 CYP2A7 CYP2D6 CYP2D6 CYP2E1 CYP2E1 MTHFR MTHFR MTHFR NAT1 NAT1 NAT1 NAT1 NAT2 NAT2 NAT2 NAT2 NAT2 TPMT TPMT TPMT MTRR SHMT1 SNP rs4736346 rs4736349 rs1799998 rs3097 rs10883783 rs6163 rs4646421 rs4886605 rs1017384 rs1042389 rs12461727 rs2032898 rs2054675 rs2279345 rs3745275 rs3844443 rs3889806 rs4803397 rs7251532 rs7251950 rs7254188 rs5751231 rs5758589 rs2515641 rs915908 rs1476413 rs1801131 rs1801133 rs4921880 rs4986783 rs7829368 rs8190845 rs1208 rs1799929 rs7013253 rs721398 rs7832071 rs1142345 rs1800462 RS1800460 RS1801394 RS1979277 Freq_Spain Freq_Cauc 0,47 0,45 0,44 0,42 0,45 0,42 0,29 0,30 0,30 0,31 0,41 0,39 0,11 0,07 0,16 0,10 0,28 0,26 0,19 0,20 0,15 0,12 0,30 0,31 0,27 0,27 0,35 0,41 0,30 0,29 0,24 0,25 0,35 0,38 0,26 0,22 0,28 0,27 0,30 0,29 0,43 0,44 0,21 0,23 0,44 0,45 0,14 0,10 0,15 0,17 0,26 0,34 0,29 0,36 0,40 0,24 0,29 0,21 0,02 0,03 0,36 0,37 0,13 0,13 0,46 0,42 0,45 0,41 0,32 0,36 0,27 0,29 0,45 0,39 0,05 0,08 G238C 0,02 0,01 G460A 0,01 0,03 A719C 0,47 0,50 0,25 0,33 40 SNPs from 14 genes No differences with other populations More genes under study 100 patients with ALL MTFR and MTX TPMT and 6MP (http://bioinfo.cnio.es/cgi-bin/cegen/frequencies.cgi) Strategy II. MTX pathway (folate analogue) 1 1- Entry 3 2 2- Degradation 3- target 4- metabolyze 4 5-…………….. …………. They study 32 genes from this pathway and identify some of them associated to MTX resistence. They found differences among ALL subtypes. Kager et al. J Clin Invest 2005 Strategy III. Genome Wide Approach Global gene expression profiling using DNA microarrays can identify: - genes with levels of expression that are related to drug response. - New drug targets It is a complementary strategy to the identification of SNPs in genes that alter protein function and drug response. Expression Profiling of T-Cell Lymphomas Differentiates Peripheral and Lymphoblastic Lymphomas and Defines Survival Related Genes LB PTCL Treatment response/ survival Genetic signature: 6 genes Median OS = 10 months Funciones de supervivencia 1,2 1,0 >10 m ,8 ,6 ,4 SUP10 <10 m NFkB 20, 00 ,2 20, 00-censurado 0,0 10, 00 P=0.0001 -, 2 10, 00-censurado -10 0 10 20 30 40 50 60 OS Martinez Delgado et al.Clin. Cancer Res, 2004. 165 genes differenciate both groups A cluster of CYP3As genes is associated with evolution CYP3A4 CYP3A7 CYP51 CYP8B1 Martinez Delgado et al. Leukemia 2005 Normalized CYP3A4 expression Expression of CYP3A4 is associated to survival of PTCLs PTCLs Log Rank p=0.001 •CYP3A4 is an important drug metabolizing enzyme, CYP3A4 expression in tumors could then be mediating the response to chemotherapy. •Detection of CYP3A4 expression could have clinical interest by identifying tumors more resistant to chemotherapy at the time of diagnosis. An alternative treatment? Martinez Delgado et al. (in preparation) Periferal T-cell lymphomas: HSP90 as drug target HSP90 is a chaperone HSP family inhibits apoptotic pathways 1 Overexpression of HSP90 - bad prognosis 2 3 4 5 PROLIFERATION Genes correlated to proliferation not specifically related to cell cycle regulation: HSP90 6 7 Inhibitors of HSP90 (17AAG) under study -No effect in normal lymphocytes 8 -Good response in peripheral T cell lines 9 10 Marta Cuadros et al. In preparation Conclusions - Pharmacogenetics is starting to be introduced and applied in the clinical practice (6MP; MTX.....) - The study of the response based on multiple genes (polygenic model) is now underway - Pharmacogenomics permits the identification of new therapeutic targets and groups of genes that modulate the pharmacological response. - It is still necessary to validate data. Problems with population variability, techniques, platforms etc.... Acknowledgements Genotyping Lab Human Genetics Lab: Lara P. Fernandez Eva Barroso Goria Ribas Beatriz Martinez Marta Cuadros CeGen Madrid Genotyping Lab: Emilio Gonzalez Roger Milner Ana Gonzalez Charo Jesus Mari Endocrine Group: Mercedes Robledo Fátima Mercadillo Cristina Rodriguez