16201620
421421
240240
162042
1
240
162042
1
240
(A) wildtype or DNA contact mutants
(B) structural mutants
THERAPEUTIC STRATEGIES DIRECTED AT
p53
TUMORS BEARING p53 MUTATIONS
Gene therapy with wt p53
E1A
E1B
pRb
E1B 55kDa
E1B 19kDa
p53
ADENOVIRUSAPOPTOSIS
DEGRADATION
E1A
E1B
REPLACED BY DA p53wt
rAd-p53
APOPTOSIS
CELL CYCLE ARREST
DRAWBACKS IN THE USE OF ADENOVIRALVECTORS FOR GENE THERAPY
Transient gene expression (14-21d)Prevalenceof neutralizing antibodiesAccess to tumor cells
TUMORS BEARING p53 MUTATIONS
Gene therapy with wt p53
Selectively replicating oncolytic viruses (Onyx-015)
THERAPEUTIC STRATEGIES DIRECTED AT
p53
TUMORS BEARING p53 MUTATIONS
Gene therapy with wt p53
Selectively replicating oncolytic viruses (Onyx-015)
Direct activation of p53 target gene products
(p21waf1; Bax)
THERAPEUTIC STRATEGIES DIRECTED AT
p53
pharmacological rescue of mutant p53 protein:
Hsp90 inhibitors
others
E1A
E1B
pRb
E1B 55kDa
E1B 19kDa
p53
ADENOVIRUSAPOPTOSIS
DEGRADATION
E1A
E1BONYX-015
pRb
TUMORS BEARING p53 MUTATIONS
Gene therapy with wt p53
Selectively replicating oncolytic viruses (Onyx-015)
Direct activation of p53 target gene products
(p21waf1; Bax)
THERAPEUTIC STRATEGIES DIRECTED AT
p53
PRIMA-1
(p53 reactivation and induction of massive apoptosis)
Block of E6 expression
Inhibition of Mdm2 expression
Inhibition of Mdm2 function
TUMORS BEARING wildtype p53
p53 response activation
THERAPEUTIC STRATEGIES DIRECTED AT
p53
FIGURE 1. Mdm2/Mdmx heterodimers are more effective p53
ubiquitin ligases than Mdm2 homodimers
RITA (Reactivation of p53 and Induction of Tumor cell Apoptosis)
20
BORTEZOMIB (VELCADE®)
Block of E6 expression
Inhibition of Mdm2 expression
Inhibition of Mdm2 function
TUMORS BEARING wildtype p53
p53 response activation
THERAPEUTIC STRATEGIES DIRECTED AT
p53
Block of p53 nuclear trafficking (leptomycin B)
TUMORS BEARING wildtype p53
p53 response activation
Block of E6 expression
Inhibition of Mdm2 expression
Inhibition of Mdm2 function
THERAPEUTIC STRATEGIES DIRECTED AT
p53
pifithrin-