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-