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Page 1: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 2: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 3: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 4: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 5: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene

PUMA

NOXA

Page 6: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 7: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 8: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene

Dominant-negative missense p53 gene mutation

Upstream tumour suppressor gene mutation (ATM)

Oncogene amplification (MDM2)

Viral oncogene amplification (HPV E6)

INACTIVATION OF THE p53 PATHWAY

Page 9: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 10: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 11: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 12: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 13: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene

Acetylation

Page 14: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 15: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 16: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 17: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 18: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 19: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 20: PUMA NOXA 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 21: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 22: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene

STRATEGIE TERAPEUTICHE BASATE SU p53

TUMORI CHE PRESENTANO MUTAZIONI DI p53

terapia genica con p53 wildtype

Page 23: PUMA NOXA 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

ADENOVIRUSAPOPTOSI

DEGRADAZIONE

E1A

E1B

SOSTITUITI DA p53wt

rAd-p53

APOPTOSI

ARRESTOdel

CICLO CELLULARE

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

PROBLEMI CONNESSI CON L’USO DI ADENOVIRUS

COME VETTORI PER LA TERAPIA GENICA

espressione genica transiente (14-21 gg)prevalenza di anticorpi neutralizzantiaccessibilità alle cellule tumorali

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

STRATEGIE TERAPEUTICHE BASATE SU p53

TUMORI CHE PRESENTANO MUTAZIONI DI p53

terapia genica con p53 wildtype

virus oncolitici a replicazione selettiva (Onyx-015)

Page 26: PUMA NOXA 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

ADENOVIRUSAPOPTOSI

DEGRADAZIONE

E1A

E1BONYX-015

pRb

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

STRATEGIE TERAPEUTICHE BASATE SU p53

TUMORI CHE PRESENTANO MUTAZIONI DI p53

terapia genica con p53 wildtype

virus oncolitici a replicazione selettiva (Onyx-015)

imitazione dei prodotti di geni regolati da p53

(p21waf1; Bax)

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

STRATEGIE TERAPEUTICHE BASATE SU p53

TUMORI CHE PRESENTANO MUTAZIONI DI p53

terapia genica con p53 wildtype

virus oncolitici a replicazione selettiva (Onyx-015)

imitazione dei prodotti di geni regolati da p53

recupero farmacologico della proteina p53 mutata:

inibitori di Hsp90

altri

Page 29: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 30: PUMA NOXA 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 31: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 32: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene

STRATEGIE TERAPEUTICHE BASATE SU p53

TUMORI CHE PRESENTANO p53 wildtype

attivazione della risposta di p53

Page 33: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene

STRATEGIE TERAPEUTICHE BASATE SU p53

TUMORI CHE PRESENTANO p53 wildtype

attivazione della risposta di p53

blocco dell’espressione di E6

Page 34: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene

STRATEGIE TERAPEUTICHE BASATE SU p53

inibizione dell’espressione di Mdm2

inibizione della funzione di Mdm2

TUMORI CHE PRESENTANO p53 wildtype

attivazione della risposta di p53

blocco dell’espressione di E6

Page 35: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 36: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 37: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 38: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 39: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 40: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 41: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene

STRATEGIE TERAPEUTICHE BASATE SU p53

blocco del trafficking nucleare di p53 (leptomicina B)

TUMORI CHE PRESENTANO p53 wildtype

attivazione della risposta di p53

blocco dell’espressione di E6

inibizione dell’espressione di Mdm2

inibizione della funzione di Mdm2

Page 42: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 43: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 44: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 45: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 46: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene
Page 47: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene

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