assessing and managing toxicities of molecularly targeted agents rome, march 28-29, 2008 target...
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Assessing and Managing Toxicities of Molecularly Targeted Agents
Rome, March 28-29, 2008
Target selectivity of molecularly targeted agents
Massimo Lopez
Istituto Nazionale Tumori “Regina Elena”, Roma
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Corpora non agunt
nisi fixata
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Primi agenti antitumorali
1. Mostarda azotata (1942)
2. Aminopterina (1947)
3. Tioguanina (1950)
4. Mercaptopurina (1951)
5. Fluorouracile (1957)
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Sviluppo della chemioterapia
1. Agenti alchilanti
2. Antimetaboliti
3. Antibiotici antitumorali
4. Analoghi del platino
5. Agenti antimicrotubuli
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Esistono differenze tra la cellula normale e quella neoplastica?
1. Assenza di differenze fondamentali da un punto di vista biochimico e fisiologico
2. Utilizzazione da parte della cellula tumorale degli stessi meccanismi a disposizione della cellula normale per crescere e moltiplicarsi
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I modelli concettuali
Il modello di Skipper-Schabel
Il modello di Delbruck-Luria
Il modello di Goldie-Coldman
Il modello di Norton-Simon
Il modello di Roger Day
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Incremento della distribuzione del farmaco nel tessuto tumorale
1. Profarmaci (capecitabina)
2. Appropriati sistemi di trasporto
A. Active targeting : Mab
B. Passive targeting: Liposomi
Polimeri biodegradabili
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Azione selettiva dei farmaci antitumorali
1. Azione su vie metaboliche selezionate2. Differenze nella velocità di proliferazione tra
cellule tumorali e cellule normali3. Tossicità selettiva in rapporto alle varie fasi del
ciclo cellulare4. Schedule di combinazione dei farmaci in
grado di potenziare al massimo l’intensità del trattamento
5. Incremento della distribuzione del farmaco nel tessuto tumorale
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Il cancro
come
malattia genetica
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Bersagli molecolari
Molecular targets
Terapia molecolare
Molecularly targeted therapy
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What is targeted therapy?
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Drug + Molecular target
=
Targeted Therapy
Targeted therapy is a therapy with a specific molecular target
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Specificità del farmaco
1. Automazione delle procedure
2. Sintesi combinatoria
3. Librerie combinatoriali di farmaci antitumorali
4. Possibilità di identificare una sostanza chimica specifica per 1/1000 possibili stati conformazionali di una proteina
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Specificità del bersaglio molecolare
Sequenza aminoacidica specifica della cellula tumorale
Presenza in tutti i pazienti affetti da una determinata neoplasia
Presenza nel 100% delle cellule tumorali di ogni paziente
Conferimento alla cellula neoplastica di un vantaggio replicativo selettivo
Dipendenza delle cellule tumorali dalla proteina bersaglio
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Terapia molecolare
Dobbiamo con questo termine intendere una terapia che ha un
solo bersaglio molecolare?
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Terapia molecolare
Quale livello di specificità?
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Razionale della terapia molecolare a bersaglio multiplo
1. Percorsi molecolari multipli attivati nei tumori solidi2. Risultati sub-ottimali con agenti singoli3. Acquisizione di resistenza dopo iniziale risposta ad un
agente singolo4. Uso di agenti a bersaglio multiplo da soli o in
combinazione con farmaci citotossici5. Sviluppo di agenti a bersaglio multiplo più rapido e
meno costoso6. Maggiore tossicità degli agenti a bersaglio multiplo
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Tipi di bersagli cellulari
1. Alterazioni molecolari geneticamente definite
2. Molecole o percorsi molecolari generali attivati nella cellula neoplastica
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Le sei capacità acquisite essenziali della cellula neoplastica
1. Auto-sufficienza dei segnali di crescita
2. Insensibilità ai segnali inibitori della crescita
3. Elusione della morte cellulare programmata
4. Potenziale replicativo illimitato
5. Neoangiogenesi
6. Invasione e metastasi
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Requisiti essenziali della terapia molecolare
1. Deve essere rivolta contro un processo biologico importante (una o più molecole)
2. Il bersaglio deve essere misurabile, qualitativamente o quantitativamente
3. Il bersaglio deve essere correlato all’evoluzione della neoplasia (validazione clinica)
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Validazione clinica della terapia molecolare
1. Selezione appropriata dei pazienti da trattare
2. Approfondita conoscenza dei meccanismi molecolari operativi nella specifica neoplasia
3. Collaborazione tra ricercatori di laboratorio, oncologi e patologi con validazione clinica precoce nel processo di sviluppo
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Agenti a bersaglio molecolare. I
1. Azione antimetastatica e inibitrice della crescita cellulare: effetto citostatico
2. Azione su bersagli molto specifici: bassa tossicità sui tessuti normali, alto indice terapeutico
3. Dose biologicamente attiva piuttosto che dose massima tollerata
4. Necessità di un test affidabile per misurare il bersaglio
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Agenti a bersaglio molecolare. II
5. Necessità di un test validato per valutare l’inibizione del bersaglio
6. Necessità di trattamenti prolungati per essere efficaci
7. Efficacia spesso maggiore in associazione ad altri farmaci
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Phase 0 clinical trials
A phase 0, or target development trial, is a
first-in-human early phase I trial designed
to study the pharmacodynamic (PD) and
pharmacokinetic (PK) properties of a drug.
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Studio di fase 0 con dose singola del farmaco in studio
Farmaco
Prelievo di PBMC per analisi
farmacodinamicaPrima
0 h 2 h 4 h 7 h 24 h
Dopo
Prelievo di sangue per analisi
farmacocinetica Prelievi multipli
Biopsie del tumore per valutazione
farmacodinamica Prima 3-6 h dopo
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Differenze tra studi di fase 0 e fase I. I
Obiettivo primario Stabilire la DMT Modulazione del bersaglio o imaging del bersaglio
Incremento della dose Valutazione della tossicità Ottenere la concentrazione plasmatica desiderata per inibire il bersaglio
Studio preclinico di In genere non effettuato Richiesto per avere datibiomarcatori farmacocinetici e
farmacodinamici
Test di valutazione di In genere non sono valutati Sono effettuati (± studi di biomarcatori marcatori farmacodinamici imaging) per stabilire il
meccanismo d’azione nei campioni di tessuto del paziente
Fase I Fase 0
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Differenze tra studi di fase 0 e fase I. II
Numero di pazienti In genere > 20 10 - 15
Dosaggio Multiplo Limitato
Beneficio terapeutico Non atteso, ma possibile Nessuno
Biopsie del tumore Opzionali Necessarie biopsie seriate
Analisi farmacocinetica/ Effettuata alla fine dello Effettuata in tempo realefarmacodinamica dello studio
Fase I Fase 0
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Sviluppo dei farmaci in oncologia
Agenti tradizionali
Studi preclinici
Fase I n =30
Fase II
n =300
Fase III
n =3000
FDA EMEA
Agenti a bersaglio molecolare
Studi preclinici
Fase 0 n = x (10-15)
Fase 1-2 n = 5-10 x
Fase III
n = 50-100 x
FDA EMEA
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Target selectivity of targeted agents
NO
YES
• Targeted agents in untargeted diseases
• Studies with results statistically significant and clinically insignificant
Targeted agents in targeted diseases