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Agnusdei, Valentina (2013) Selective targeting of NOTCH-1 for therapeutic purposes in xenograft models of T-acute lymphoblastic leukemia. [Tesi di dottorato]

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Abstract (inglese)

T-cell acute lymphoblastic leukemia (T-ALL) is an heterogeneous disease, characterized by several genetic alterations and polymorphic clinical features both in children and adults. The Notch pathway, an evolutionary conserved pathway involved in many biological processes including T cell differentiation, has been implicated in the pathogenesis of this disease. Notably, about 50-55% of T-ALL samples show increased Notch1 activity, due to mutations in NOTCH1 or FBW7 genes. Among T-ALL patients, only 70-80% of children and 40% of adults reach long-term remission, therefore new therapeutic approaches are required. Here, we investigated the biologic and therapeutic effects of a human Notch1-specific neutralizing antibody in xenograft models of pediatric T-ALL, obtained from patients with different clinical features and NOTCH1/FBW7 mutational status. We demonstrated that anti-Notch1 treatment greatly delayed engraftment of T-ALL cells bearing NOTCH1/FBW7 mutations, including samples derived from relapsed and clinically difficult-to-treat patients. In these xenografts we observed increased levels of apoptosis, decreased proliferation of leukemic cells and a marked inhibitory effects on Notch transcriptional profile. Moreover, modulation of T-ALL cells metabolism was detected following anti-Notch1 therapy. Serial transplantation experiments suggested that anti-Notch1 therapy could compromise leukemia initiating cell functions and a preliminary experiment showed that resistance may arise in a regimen of continuous administration of anti-Notch1 mAb. Finally, we demonstrated that combination of anti-Notch1 and dexamethasone – a leading drug in T-ALL treatment - could further improve therapeutic effect.
Altogether these results indicate that NOTCH1/FBW7 mutations identify suitable candidates for Notch targeted therapy and highlight the potential of Notch target genes and CD7 expression as candidate predictive markers of response to anti-Notch1 therapy.

Abstract (italiano)

La leucemia linfoblastica acuta a cellule T (T-ALL) è una malattia eterogenea caratterizzata da diverse alterazioni genetiche e caratteristiche cliniche, sia in età pediatrica che adulta. Un ruolo importante in questo tipo di neoplasia è ricoperto dal pathway di Notch, meccanismo evolutivamente conservato coinvolto in numerosi processi biologici tra cui il differenziamento dei linfociti T; difatti in circa il 50-55% dei pazienti affetti da T-ALL si riscontra una mutazione attivante nel gene NOTCH1 o a carico di FBW7. Dal momento che solo il 70-80% dei bambini e il 40% degli adulti affetti da questo tipo di leucemia riesce a raggiungere la remissione a lungo termine, e’ necessario sviluppare ed adottare nuove strategie terapeutiche per poter curare anche i pazienti refrattari alle terapie convenzionali. A questo scopo abbiamo analizzato gli effetti biologici e terapeutici di un anticorpo neutralizzante specifico per il recettore Notch1 umano, avvalendoci di un modello di xenotrapianto di T-ALL. Tale modello è stato generato nel nostro laboratorio utilizzando campioni ottenuti da pazienti pediatrici con caratteristiche cliniche differenti e presentanti diverso stato mutazionale di NOTCH1/FBW7. Il trattamento con anti-Notch1 si è rivelato efficace nel contrastare la crescita della leucemia dei campioni con mutazione di NOTCH1/FBW7, compresi campioni derivati da pazienti in ricaduta o poco responsivi alle terapie convenzionali. In seguito alla somministrazione di anti-Notch1, in questi xenotrapianti abbiamo osservato un aumento dei livelli di apoptosi, una riduzione della proliferazione, un effetto inibitorio molto marcato sui profili trascrizionali dei geni target di Notch e inoltre una modulazione del metabolismo cellulare delle cellule leucemiche. Gli esperimenti di inoculo seriale indicano che la terapia con anti-Notch1 può compromettere la capacità di dare origine a leucemia delle cellule di T-ALL residue dopo il trattamento. Inoltre un esperimento preliminare ha rivelato che la somministrazione continua dell’anticorpo anti-Notch1 può causare l’insorgenza di fenomeni di resistenza alla terapia. Infine abbiamo dimostrato che la combinazione di anti-Notch1 e desametasone, un farmaco comunemente utilizzato nel trattamento delle T-ALL, può ulteriormente migliorare l’efficacia terapeutica.
Nel complesso, i nostri risultati indicano che la presenza di mutazioni in NOTCH1/FBW7 identifica dei candidati che potrebbero beneficiare di una terapia mirata contro Notch1 e sottolinea la potenzialità del valutare l’espressione dei geni target di Notch e del CD7 come marcatori predittivi della risposta terapeutica all’anti-Notch1.

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Tipo di EPrint:Tesi di dottorato
Relatore:Indraccolo, Stefano
Dottorato (corsi e scuole):Ciclo 25 > Scuole 25 > ONCOLOGIA E ONCOLOGIA CHIRURGICA
Data di deposito della tesi:29 Gennaio 2013
Anno di Pubblicazione:29 Gennaio 2013
Parole chiave (italiano / inglese):Notch1, T-ALL, targeted therapy, predictive biomarkers
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/06 Oncologia medica
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche
Codice ID:5686
Depositato il:14 Ott 2013 14:01
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