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De Mattia, Elena (2011) Farmacogenetica dell'irinotecano in associazione con fluoropirimidine (Folfiri) nel trattamento di pazienti con carcinoma colonrettale metastatico. [Tesi di dottorato]

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Abstract (inglese)

Pharmacogenetics focuses on intersubjects variability in therapeutic drug effects and toxicity depending on genetic polymorphisms.
The prodrug irinotecan (CPT-11) is a camptothecin analogue exerting its antitumor efficacy by inhibiting topoisomerse I. This compound, used for a variety of malignancies as the metastatic colorectal cancer (CRC), is characterized by a, sometimes unpredictable, severe haematological (neutropenia) and non haematological (diarrhea) toxicity and by a significant intersubjects variability in the response to the treatment, despite the established antineoplastic efficacy. The metabolic pathway of irinotecan is complex and the main steps are: 1) activation of CPT-11 to SN-38 (hCES1 and 2); 2) oxidation of CPT-11 to minor inactive metabolites APC and NPC (CYP3A4 and CYP3A5); 3) detoxification by glucuronidation of SN-38; (UGT1A1, UGT1A7 and UGT1A9); 4) cellular uptake and excretion of the irinotecan and its metabolites (OATP1B1, MDR1, MRP1, MRP2 and BCRP). Polymorphic sequences in the genes encoding for some of these proteins have been described. In particular, scientific research and international drug agencies have focused on the role of UGT1A1*28 polymorphism as predictive marker of irinotecan therapy outcome, suggesting its possible use for personalizing the treatment. On this ground, our group have generated important results that underline and confirm the relevance of this genetic determinant (Toffoli G et al. JCO 2010, Cecchin E et al. JCO 2009, Toffoli G et al. JCO 2006). Aim of this study was to expand the pharmacogenetic analysis defining the impact of genetic polymorphisms of cytochromes, UGT1As and transporters related genes, in determining the outcome of irinotecan therapy in metastatic CRC patients, in relation to UGT1A1*28 variant. The retrospective analysis was conducted on 250 Caucasian patients with metastatic CRC, homogeneously treated with an irinotecan including regimen (irinotecan, 5-fluorouracil and folinic acid, FOLFIRI regimen), undergoing pharmacogenetic and clinical monitoring; 71 of them were also investigated for pharmacokinetics. A set of 50 genetic polymorphisms, involved in oxidative metabolism, glucuronidation pathway and transport of the drug and its metabolites were investigated, inferring genotypes/diplotypes to each patient. Genotyping was performed by Pyrosequencing, allelic discrimination (TaqMan technology), and fragment analysis. Bioinformatic tools were employed to perform linkage disequilibrium and haplotype investigation. Moreover, 71 patients underwent pharmacokinetic analysis by HPLC, and the pharmacokinetics parameters were calculated adopting the non-compartmental model. Clinical parameters of toxicity (by NCI-CTC scale) and response to the therapy (by WHO criteria) were monitored all along the study. Follow-up of the patients was carried out in order to collect data about time to progression (TTP) and overall survival (OS). Univariate and multivariate analyses were performed to discover possible significant association of the genetic variants with 1) acute (first cycle) and overall (entire course of therapy) haematological and non haematological toxicity, particularly neutropenia and diarrhea, 2) clinical benefit (CB) and response rate (RR), 3) TTP and OS, and 4) pharmacokinetics profile of CPT-11, SN-38 e SN-38G.
This study highlighted a set of genetic markers that, in combination with classic clinico-demographic factors, could predict the clinical outcome of the FOLFIRI treatment. In particular, the following genetic determinants were identified 1) hematological toxicity (neutropenia): a differential risk of developing acute and/or cumulative toxic effects correlated with the genetic variants of UGT1A (UGT1A7*3, UGT1A9*22, UGT1A haplotype I) and transporters ABCC1 (1303C>A), ABCC2 (haplotype II) and ABCG2 (haplotype I) genes; 2) haematological toxicity (diarrhea): an important predictive role was highlighted for genetic markers of membrane carriers with an increased risk to develop acute and/or cumulative adverse events for polymorphisms of ABCC1 (1684C>T, IVS18-30G>C) and ABCG2 (15994G>A) and, on the contrary, a lower risk for ABCC2 1023G>A; 3) Tumour response: UGT1A1*28 emerged as the only genetic determinant of CB, and it was also associated to response rate together with other genetic markers of UGT1A (haplotype II) and transporters ABCC1 (2012G>T), ABCC2 (1249G>A, haplotype II), ABCG2 (-15622C>T, ABCG2 -15994G>A, haplotype III) and OATP1B1 (-11187G>A); 4) TTP: UGT1A1*28 and UGT1A haplotype II correlated with longer TTP.
An essential support to the results obtained in this work, derived from the pharmacokinetic analysis. Moreover, this pharmacogenetic study validated the efficacy of haplotype approach.
In conclusion, in this work of thesis, an innovative predictive role for several genetic markers of membrane transporters was defined and the predominant clinical impact of UGT1A variants, in particular on antitumour efficacy and TTP, was confirmed. After validation in prospective studies, a possible application of these parameters in the clinical practice will be useful to design a tailored FOLFIRI treatment based on peculiar characteristics of each metastatic CRC patient.

Abstract (italiano)

La farmacogenetica studia il ruolo dei polimorfismi genici nel determinare la variabilità interindividuale che si osserva nell’esito clinico di un trattamento farmacologico sia in termini di tossicità che di efficacia della terapia.
L’irinotecano (CPT-11) è un profarmaco, derivato semisintetico della campotecina, che agisce come inibitore della topoisomerasi I. Tale composto, impiegato per il trattamento del carcinoma colonrettale (CCR) metastatico, nonostante la sua provata efficacia antitumorale, presenta degli effetti tossici particolarmente significativi, sia di tipo ematologico (neutropenia) che non ematologico (diarrea), ed una notevole variabilità intersoggettiva nella risposta al trattamento. L’irinotecano presenta un complesso pathway metabolico i cui steps principali sono: 1) attivazione di CPT-11 a SN-38 (hCES1, hCES2); 2) ossidazione di CPT-11 a derivati non farmacologicamente attivi, APC e NPC (CYP3A4, CYP3A5); 3) detossificazione tramite glucuronazione di SN-38 (UGT1A1, UGT1A7, UGT1A9); 4). escrezione ed uptake cellulare del farmaco e dei suoi metaboliti (OATP1B1, MDR1, MRP1, MRP2, BCRP). Per alcune di queste proteine, sono stati descritti diversi polimorfismi genici fenotipicamente importanti. In particolare, nel mondo scientifico e a livello degli organi regolatori internazionali del farmaco, grande attenzione è stata posta sul ruolo della variante UGT1A1*28 come marker predittivo dell’esito della terapia con irinotecano ipotizzando un suo utilizzo per la definizione di una terapia personalizzata. In questo ambito il nostro gruppo ha prodotto importanti risultati che sottolineano la rilevanza di questo determinante genico (Toffoli G et al. JCO 2010, Cecchin E et al. JCO 2009, Toffoli G et al. JCO 2006). Lo scopo di questa tesi è quello di ampliare l’analisi farmacogenetica dell’irinotecano, definendo l’impatto di varianti geniche dei citocromi, degli UGT1As e dei trasportatori nel modulare l’outcome del trattamento con FOLFIRI (CPT-11, 5-fluorouracile, acido folico), in pazienti con CCR metastatico, in rapporto al polimorfismo UGT1A1*28. L’analisi, di tipo retrospettico, è stata condotta su 250 pazienti caucasici affetti da CCR metastatico omogeneamente trattati con regime FOLFIRI, sui quali è stato effettuato un monitoraggio farmacogenetico e clinico. 71 individui sono stati inclusi nell’analisi farmacocinetica. I pazienti sono stati analizzati per un set di 50 polimorfismi di geni coinvolti nel metabolismo ossidativo, nel processo di glucuronazione e nei meccanismi di trasporto. La genotipizzazione è stata realizzata tramite Pyrosequencing, discriminazione allelica (tecnologia TaqMan) e analisi dei frammenti. Tramite strumenti bioinformatici è stato effettuato anche uno studio di linkage disequilibrium ed aplotipico. 71 pazienti sono stati analizzati per la farmacocinetica tramite metodiche di HPLC, e i parametri farmacocinetici sono stati calcolati adottando un modello non-compartimentale. I dati clinici di tossicità (scala NCI-CTC) e di risposta (criteri WHO) alla terapia, sono stati monitorati durante tutta la durata dello studio. I pazienti sono stati seguiti al follow-up in modo da valutare il dato di tempo alla progressione tumorale (TTP) e sopravvivenza (OS). Tramite un’analisi univariata e multivariata si è valutato, quindi, il ruolo dei vari marker genici nell’influenzare: 1) la tossicità ematologica e non ematologica, acuta (primo ciclo di terapia) e cumulativa (intero corso del trattamento), con particolare attenzione alla neutropenia e diarrea; 2) clinical benefit (CB) e response rate (RR); 3) TTP e OS; e 4) profilo farmacocinetico di CPT-11, SN-38 e SN-38G.
Il lavoro di questa tesi ha permesso di determinare, assieme ai classici fattori clinico-demografici, nuovi marcatori genetici dell’outcome clinico della terapia effettuata con regime FOLFIRI. In particolare si sono identificati i seguenti determinati genici 1) Tossicità ematologica (neutropenia): un rischio differenziale di sviluppare effetti avversi acuti e/o cumulativi si è dimostrato essere associato a varianti di UGT1A (UGT1A7*3, UGT1A9*22, UGT1A aplotipo I) e dei trasportatori ABCC1 (1303C>A), ABCC2 (aplotipo II) e ABCG2 (aplotipo I) 2) Tossicità non ematologica (diarrea): un ruolo predittivo importante è stato evidenziato per alcuni markers genici dei trasportatori con un maggior rischio di eventi avversi acuti e/o cumulativi correlato a ABCC1 (1684C>T, IVS18-30G>C) e ABCG2 (15994G>A) e, al contrario, un minor rischio associato a ABCC2 (1023G>A) 3) Risposta tumorale: UGT1A1*28 è risultato l’unico determinante genetico predittivo del CB; lo stesso polimorfismo assieme ad altri markers genetici di UGT1A (aplotipo II) e di proteine trasportatrici ABCC1 (2012G>T), ABCC2 (1249G>A, aplotipo II), ABCG2 (-15622C>T, ABCG2 -15994G>A, aplotipo III) e OATP1B1 (-11187G>A), sono risultati significativi nel modulare la riposta obbiettiva alla terapia. 4) TTP: un ruolo prognostico è stato dimostrato per UGT1A1*28 e UGT1A aplotipo II, entrambi correlati con un minor rischio di andare incontro a progressione di malattia. Un supporto ai risultati ottenuti è derivato dall’analisi farmacocinetica. Il lavoro ha consentito, inoltre, di valutare e confermare la validità dell’approccio aplotipico.
In conclusione, il lavoro di questa tesi ha permesso di definire nuovi marker genici legati al trasporto del farmaco confermando l’impatto clinico delle varianti di UGT1A sull’outcome del trattamento, con particolare riferimento alla risposta tumorale e al TTP. La validazione dei risultati ottenuti potrà fornire agli oncologi clinici uno strumento utile per ottimizzare e personalizzare la terapia di pazienti con CCR metastatico trattati con irinotecano in regime FOLFIRI.

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Tipo di EPrint:Tesi di dottorato
Relatore:Giusti, Pietro
Correlatore:Toffoli, Giuseppe - Cecchin, Erika
Dottorato (corsi e scuole):Ciclo 23 > Scuole per il 23simo ciclo > SCIENZE FARMACOLOGICHE > FARMACOLOGIA MOLECOLARE E CELLULARE
Data di deposito della tesi:NON SPECIFICATO
Anno di Pubblicazione:Aprile 2011
Parole chiave (italiano / inglese):farmacogenetica/pharmacogenetics irinotecano/irinotecan carcinoma colonrettale/ colorectal cancer
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/14 Farmacologia
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Farmacologia ed Anestesiologia "E. Meneghetti"
Codice ID:3328
Depositato il:19 Lug 2011 17:18
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