PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation...

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

Acetylation

16201620

421421

240240

162042

(A) wildtype or DNA contact mutants

(B) structural mutants

STRATEGIE TERAPEUTICHE BASATE SU p53

TUMORI CHE PRESENTANO MUTAZIONI DI p53

terapia genica con p53 wildtype

E1B 55kDa

E1B 19kDa

ADENOVIRUSAPOPTOSI

DEGRADAZIONE

SOSTITUITI DA p53wt

rAd-p53

APOPTOSI

ARRESTOdel

CICLO CELLULARE

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

virus oncolitici a replicazione selettiva (Onyx-015)

E1B 55kDa

E1B 19kDa

ADENOVIRUSAPOPTOSI

DEGRADAZIONE

E1BONYX-015

imitazione dei prodotti di geni regolati da p53

(p21waf1; Bax)

imitazione dei prodotti di geni regolati da p53

recupero farmacologico della proteina p53 mutata:

inibitori di Hsp90

PRIMA-1

(p53 reactivation and induction of massive apoptosis)

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

blocco del trafficking nucleare di p53 (leptomicina B)

inibizione dell’espressione di Mdm2

inibizione della funzione di Mdm2

pifithrin-

PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation...

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