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Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene...

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Page 1: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 2: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 3: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 4: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 5: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 6: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 7: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 8: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 9: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 10: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 11: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 12: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 13: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 14: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 15: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 16: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 17: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.

16201620

421421

240240

162042

1

240

162042

1

240

(A) wildtype or DNA contact mutants

(B) structural mutants

Page 18: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 19: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 20: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 21: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.

THERAPEUTIC STRATEGIES DIRECTED AT

p53

TUMORS BEARING p53 MUTATIONS

Gene therapy with wt p53

Page 22: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.

E1A

E1B

pRb

E1B 55kDa

E1B 19kDa

p53

ADENOVIRUSAPOPTOSIS

DEGRADATION

E1A

E1B

REPLACED BY DA p53wt

rAd-p53

APOPTOSIS

CELL CYCLE ARREST

Page 23: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.

DRAWBACKS IN THE USE OF ADENOVIRALVECTORS FOR GENE THERAPY

Transient gene expression (14-21d)Prevalenceof neutralizing antibodiesAccess to tumor cells

Page 24: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.

TUMORS BEARING p53 MUTATIONS

Gene therapy with wt p53

Selectively replicating oncolytic viruses (Onyx-015)

THERAPEUTIC STRATEGIES DIRECTED AT

p53

Page 25: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.

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

Page 26: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.

E1A

E1B

pRb

E1B 55kDa

E1B 19kDa

p53

ADENOVIRUSAPOPTOSIS

DEGRADATION

E1A

E1BONYX-015

pRb

Page 27: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.

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

Page 28: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 29: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.

PRIMA-1

(p53 reactivation and induction of massive apoptosis)

Page 30: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 31: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.

Block of E6 expression

Inhibition of Mdm2 expression

Inhibition of Mdm2 function

TUMORS BEARING wildtype p53

p53 response activation

THERAPEUTIC STRATEGIES DIRECTED AT

p53

Page 32: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 33: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 34: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 35: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.

FIGURE 1. Mdm2/Mdmx heterodimers are more effective p53

ubiquitin ligases than Mdm2 homodimers

Page 36: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 37: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.

RITA (Reactivation of p53 and Induction of Tumor cell Apoptosis)

Page 38: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 39: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 40: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 41: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.

20

Page 42: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 43: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.

BORTEZOMIB (VELCADE®)

Page 44: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 45: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 46: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 47: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.

Block of E6 expression

Inhibition of Mdm2 expression

Inhibition of Mdm2 function

TUMORS BEARING wildtype p53

p53 response activation

THERAPEUTIC STRATEGIES DIRECTED AT

p53

Page 48: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.

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

Page 49: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 50: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 51: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 52: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 53: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.
Page 54: Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.

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