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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