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Abstract (english)

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive tumor with increasing incidence in industrialized countries, because of previous widespread asbestos exposure and long latency time before symptoms appearance. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) belongs to the tumor necrosis factor (TNF) family of death ligands; it was identified as a promising anticancer agent thanks to its property of killing cancer cells while sparing normal cells. Conflicting evidences about MPM resistance rather than sensitivity to TRAIL-induced apoptosis were previously reported. While TRAIL-dependent apoptosis is thought to be p53-independent, p53 wild type cancer cells can be sensitized to TRAIL through p53 activation. In contrast to most solid tumors, MPM cells frequently express wild type p53, thus p53 reactivation might be considered as an effective strategy to sensitize MPM cells to TRAIL-dependent apoptosis. DNA-damaging agents such as chemotherapy or radiotherapy and other agents targeting negative regulators of p53, may be considered as useful strategies to reactivate p53. Murine Double Minute 2 (MDM2) is a transcriptional target of p53: once activated, MDM2 binds p53 to the amino-terminus, targeting it for ubiquitylation and subsequent proteasomal degradation. Recently, many researchers have investigated a possible role of MDM2 in promoting tumor neoangiogenesis (Vascular Endothelial Growth Factor, VEGF; hypoxia inducible factor, HIF1alpha). Thus MDM2 might be a promising target for anticancer treatment because of its antiapoptotic and proangiogenetic role. The poor prognosis of affected patients, the lack of effective treatment options, with particular reference to biologic drugs, the absence of predictive markers for targeted treatment and the lack of knowledge about the basis of different biological and clinical behaviour of the two main histologic subtypes, epithelioid versus non-epithelioid (sarcomatoid/biphasic), constitute the rationale for the present study.
AIMS: The first purpose of the study was to investigate new treatment options through preclinical evaluation of extrinsic apoptosis triggers (recombinant human Apo2L/TRAIL) in combination with intrinsic apoptosis inducers acting through the reactivation of p53, such as DNA-damaging agents (carboplatin/pemetrexed) or p53-MDM2 inhibitors (nutlin3-RG7112), both in vitro and in vivo. Moreover, the study aims to investigate new targets (MDM2, HIF1alpha, VEGF) for treatment in MPM tumor samples, testing possible different expression levels of such targets in the different histologic subtypes. Some morphological features, such as inflammation, necrosis and proliferation were quantified in the different histotypes and correlated with MDM2 and HIF1alpha. Finally, correlations between molecular data and clinical features were performed.
METHODS: Anticancer effects of rhApo2L/TRAIL (Amgen, Genentech) plus chemotherapy (Carboplatin/Pemetrexed) or nutlin3-RG7112 (Roche) was evaluated in different cell lines through annexin V and caspases assay, and in a Severe Combined ImmunoDeficiency (SCID) mouse model. p53 expression levels were evaluated through western blot. TRAIL receptors were evaluated through flow cytometry. Formalin-Fixed Paraffin Embedded (FFPE) chemonaive tumor samples from MPM patients were analyzed: MDM2, VEGF and HIF1alpha mRNA and protein expression levels were investigated through RT-qPCR and immunohistochemistry (IHC) with specific antibodies, respectively. Proliferation was quantified through staining with Ki67 antibodies. Necrosis and inflammation were also quantified on histological sections using a grading score. Normal pleura samples from patients undergoing diagnostic surgery for non cancer disease were used as negative controls. Clinical data of the patients under study were collected in a password-protected database: age, gender, ECOG PS (Performance Status), EORTC score, stage, systemic treatments, surgery, radiotherapy, first progression and last follow-up date, status (alive/dead).
RESULTS: In vitro and in vivo results showed a significant increase of apoptosis in cell lines and reduction of tumor volume in animal models treated with rhApo2L/TRAIL plus chemotherapy or nutlin3-RG7112 compared with those receiving single treatments. This synergistic effect was dependent on the ability of chemotherapy or nutlin3-RG7112 to increase the expression of the TRAIL receptors DR4 and DR5 in a p53 manner. Higher MDM2 and HIF1alpha IHC expression was significantly associated with sarcomatoid/biphasic histologic subtype (p=0.010 and p=0.007, respectively) with positive correlation between MDM2 and HIF1alpha expression levels (correlation coefficient=0.533; p value= 0.00626). Proliferation index was significantly higher in sarcomatoid/biphasic compared with epithelioid samples (p=0.005) and also significantly higher in tumor samples with higher MDM2 expression (p=0.008). Clinical and pathological features or biomarker did not show any correlation with prognosis, except for proliferation index and Progression Free Survival (PFS), even though the results of this exploratory analysis should be considered with caution because of the limited number of patients, the heterogeneous treatment received and the insufficient follow-up time in some patients.
CONCLUSION: Our preclinical in vitro and in vivo results confirm that reactivation of p53 by chemotherapy or p53-MDM2 inhibitors effectively sensitizes to TRAIL-dependent apoptosis in malignant pleural mesothelioma.
Our translational study in tumor samples from MPM patients confirmed different biological and pathological features and molecular targets expression in the two main histologic subtypes. It is tempting to speculate that MDM2 and Ki67 might be considered as further useful diagnostic tools to identify poor prognosis patients. Moreover, MDM2 and HIF1alpha might be considered as promising targets for anticancer treatment of MPM.

Abstract (italian)

BACKGROUND: Il mesotelioma pleurico maligno (MPM) è una neoplasia aggressiva con incidenza in aumento nei paesi industrializzati per la pregressa esposizione ad amianto e il lungo periodo di latenza tra l’esposizione e la comparsa dei sintomi. TRAIL (Tumor necrosis factor-related apoptosis-inducing ligand) appartiene alla famiglia dei ligandi di morte apoptotica di TNF (tumor necrosis factor), ed è stato recentemente identificato come promettente agente antitumorale in considerazione della sua proprietà di uccidere le cellule tumorali, risparmiando le cellule normali. Evidenze contrastanti riportano la presenza di resistenza piuttosto che di sensibilità delle cellule di mesotelioma maligno all’apoptosi mediata da TRAIL. Sebbene l’apoptosi indotta da TRAIL (via estrinseca dell’apoptosi) sembra essere indipendente da p53, alcune cellule tumorali portatrici di p53 wild-type possono essere sensibilizzate alla morte da TRAIL attraverso l’attivazione di p53 (via intrinseca dell’apoptosi). Contrariamente alla maggior parte delle neoplasie, le cellule di mesotelioma pleurico esprimono più frequentemente p53 wild-type, e quindi la riattivazione di p53 potrebbe essere una strategia efficace per sensibilizzare le cellule di mesotelioma all’apoptosi mediata da TRAIL. Agenti in grado di danneggiare il DNA (chemioterapia, radioterapia) ed altri agenti in grado di “down-regolare” gli inibitori di p53, possono essere considerati come valide strategie per riattivare p53. Murine Double Minute 2 (MDM2) è un bersaglio dell’attività trascrizionale di p53: una volta attivata, MDM2 lega il dominio ammino-terminale di p53 e la conduce al processo di ubiquitilazione e successiva degradazione proteasomica. Negli anni recenti, molti ricercatori hanno studiato un possibile ruolo di MDM2 nella attivazione di marcatori di neoangiogenesi tumorale (Vascular Endothelial Growth Factor, VEGF; hypoxia inducible factor, HIF1alpha), pertanto MDM2 potrebbe rappresentare un promettente bersaglio per il trattamento antitumorale in considerazione della sua possibile duplice attività antiapoptotica e proangiogenetica. La prognosi infausta dei pazienti affetti, l’assenza di opzioni terapeutiche efficaci, in particolare di farmaci biologici, l’assenza di marcatori predittivi di risposta ai farmaci a bersaglio molecolare, e la scarsità di conoscenze sui meccanismi che sottendono al diverso comportamento biologico e clinico dei due principali sottotipi istologici (epitelioide versus non-epitelioide), costituiscono il razionale del presente studio.
OBIETTIVI: Il primo obiettivo è stato valutare nuove opzioni terapeutiche attraverso studi preclinici in vitro ed in vivo con associazione di induttori della via estrinseca dell’apoptosi (rhApo2L/TRAIL) e induttori della via intrinseca dell’apoptosi che agiscono attraverso riattivazione di p53, come agenti danneggianti il DNA (carboplatino/pemetrexed) o inibitori del legame p53-MDM2 (nutlin3-RG7112). Secondariamente, lo studio si è proposto di ricercare l’espressione dei nuovi bersagli terapeutici (MDM2, HIF1alpha) nei campioni tumorali di pazienti affetti da mesotelioma maligno, e di valutarne la diversa espressione nei diversi sottotipi istologici. Inoltre, il progetto si è focalizzato sulla valutazione di alcuni parametri morfologici come infiammazione, necrosi ed indice proliferativo nei campioni tumorali dei diversi istotipi e sulla loro correlazione con MDM2 e HIF1alpha. Infine, sono state valutate le correlazioni tra dati molecolari e caratteristiche cliniche dei pazienti in studio.
MATERIALI E METODI: l’attività antitumorale di rhApo2L/TRAIL (Amgen, Genentech) in associazione a chemioterapia (Carboplatino/Pemetrexed) o nutlin3-RG7112 (Roche) è stata valutata in diverse linee cellulari attraverso il saggio di Annessina V e delle caspasi, e in un modello di topo Severe Combined ImmunoDeficiency (SCID). I livelli di espressione di p53 sono stati analizzati attraverso western blot. I recettori di TRAIL sono stati rilevati attraverso citofluorimetria. Campioni tumorali fissati in formalina e inclusi in paraffina da pazienti chemonaive sono stati analizzati con immunoistochimica e valutando l’espressione di mRNA per MDM2 e HIF1alpha. L’indice proliferativo è stato quantificato mediante anticorpo monoclonale di Ki67. La presenza di infiammazione e necrosi è stata valutata su sezioni istologiche. Campioni di pleura normale da pazienti sottoposti a chirurgia toracica per patologia non oncologica sono stati utilizzati come controlli negativi. I dati clinici dei pazienti in studio sono stati raccolti un un database protetto da password: età, sesso, ECOG PS (Performance Status), score prognostico EORTC, stadio, trattamenti sistemici, chirurgia, radioterapia, prima progressione, data di ultimo follow-up e status (vivo/morto).
RISULTATI: I risultati in vitro ed in vivo mostrano un significativo aumento di apoptosi in linee cellulari e riduzione di volume tumorale in modelli animali trattati con rhApo2L/TRAIL in associazione a chemioterapia o nutlin3-RG7112, confrontato ai singoli trattamenti. Tale effetto sinergico è correlato all’incremento di espressione dei recettori di TRAIL (DR4 e 5) conseguente alla riattivazione di p53 da chemioterapia o nutlin3-RG7112. Abbiamo poi valutato i livelli di espressione di MDM2 e del suo possibile target HIF1alpha in campioni tumorali di pazienti affetti da mesotelioma. I livelli di espressione di MDM2 e HIF1alpha erano significativamente più elevati nel sottotipo istologico sarcomatoide/bifasico (p=0.010 and p=0.007, respectively), ed è stata osservata una correlazione positiva tra i livelli di espressione di MDM2 e HIF1alpha (coefficiente di correlazione =0.533; p = 0.00626). Infine, l’indice proliferativo (Ki67) si è dimostrato significativamente più elevato nel sottotipo istologico sarcomatoide/bifasico rispetto a quello epitelioide (p=0.005) e significativamente più elevato nei campioni con iperespressione di MDM2 (p=0.008). Per quanto riguarda gli obiettivi esploratori del progetto, nessuna correlazione prognostica è stata osservata per alcun parametro clinico o patologico o per diversi livelli di espressione dei biomarcatori in studio, mentre è stata osservata una correlazione significativa tra i livelli di Ki67 e la sopravvivenza libera da progressione. I risultati di tale indagine esploratoria devono, comunque, essere considerati con cautela per la limitata dimensione campionaria, l’eterogeneità degli interventi terapeutici e l’insufficiente follow-up di alcuni pazienti.
CONCLUSIONI: I risultati in vitro e in vivo di questo progetto di ricerca dimostrano che la riattivazione di p53 con chemioterapia o molecole inibitrici del legame p53-MDM2 rappresenta un’efficace strategia per sensibilizzare all’apoptosi mediata da TRAIL. Lo studio traslazionale ha invece confermato diverse caratteristiche biologiche e patologiche così come differenti livelli di espressione di nuovi bersagli terapeutici nei due sottotipi istologici di MPM. MDM2 e Ki67 possono essere considerati come importanti ausili diagnostici per una migliore caratterizzazione dell’istotipo e soprattutto per identificare i tumori a peggiore prognosi. Inoltre, MDM2 e HIF1alpha potrebbero rappresentare promettenti bersagli per il trattamento del mesotelioma pleurico maligno.

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EPrint type:Ph.D. thesis
Tutor:Rea, Federico
Supervisor:Calabrese, Fiorella
Data di deposito della tesi:28 January 2015
Anno di Pubblicazione:28 January 2015
Key Words:mesothelioma, apoptosis, angiogenesis, MDM2, inflammation, necrosis, proliferation; mesotelioma, apoptosi, angiogenesi, MDM2, infiammazione, necrosi, proliferazione
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/11 Malattie dell'apparato cardiovascolare
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Cardiologiche, Toraciche e Vascolari
Istituti > Istituto di Anatomia Patologica
Codice ID:7651
Depositato il:20 Nov 2015 15:05
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