Vai ai contenuti. | Spostati sulla navigazione | Spostati sulla ricerca | Vai al menu | Contatti | Accessibilità

| Crea un account

Pasello, Giulia (2015) RESEARCH OF PREDICTIVE AND PROGNOSTIC TISSUE AND MOLECULAR MARKERS AND OF NEW THERAPEUTIC TARGETS IN MALIGNANT PLEURAL MESOTHELIOMA. [Tesi di dottorato]

Full text disponibile come:

[img]
Anteprima
Documento PDF - Versione accettata
2698Kb

Abstract (inglese)

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 (italiano)

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.

Statistiche Download - Aggiungi a RefWorks
Tipo di EPrint:Tesi di dottorato
Relatore:Rea, Federico
Correlatore:Calabrese, Fiorella
Dottorato (corsi e scuole):Ciclo 27 > scuole 27 > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > SCIENZE CARDIOVASCOLARI
Data di deposito della tesi:28 Gennaio 2015
Anno di Pubblicazione:28 Gennaio 2015
Parole chiave (italiano / inglese):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
Simple Metadata
Full Metadata
EndNote Format

Bibliografia

I riferimenti della bibliografia possono essere cercati con Cerca la citazione di AIRE, copiando il titolo dell'articolo (o del libro) e la rivista (se presente) nei campi appositi di "Cerca la Citazione di AIRE".
Le url contenute in alcuni riferimenti sono raggiungibili cliccando sul link alla fine della citazione (Vai!) e tramite Google (Ricerca con Google). Il risultato dipende dalla formattazione della citazione.

1. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21: 2636-2644. Cerca con Google

2. van Meerbeeck JP, Gaafar R, Manegold C, Van Klaveren RJ, Van Marck EA, Vincent M, Legrand C, Bottomley A, Debruyne C, Giaccone G, European Organisation for R, Treatment of Cancer Lung Cancer G, National Cancer Institute of C. Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada. J Clin Oncol 2005;23: 6881-6889. Cerca con Google

3. Bianchi C, Bianchi T. Malignant mesothelioma: global incidence and relationship with asbestos. Ind Health 2007;45: 379-387. Cerca con Google

4. Tossavainen A. National mesothelioma incidence and the past use of asbestos. Monaldi Arch Chest Dis 2003;59: 146-149. Cerca con Google

5. Tossavainen A. Global use of asbestos and the incidence of mesothelioma. Int J Occup Environ Health 2004;10: 22-25. Cerca con Google

6. Marinaccio A, Binazzi A, Cauzillo G, Chellini E, De Zotti R, Gennaro V, Menegozzo M, Mensi C, Merler E, Mirabelli D, Musti M, Pannelli F, Romanelli A, Scarselli A, Tosi S, Tumino R, Nesti M, Gruppo di lavoro ReNa M. [Epidemiological surveillance of malignant mesothelioma cases in Italy: incidence and asbestos exposure figures by the Italian mesothelioma registry (ReNaM)]. Epidemiol Prev 2007;31: 23-26. Cerca con Google

7. Peto J, Decarli A, La Vecchia C, Levi F, Negri E. The European mesothelioma epidemic. Br J Cancer 1999;79: 666-672. Cerca con Google

8. Pelucchi C, Malvezzi M, La Vecchia C, Levi F, Decarli A, Negri E. The Mesothelioma epidemic in Western Europe: an update. Br J Cancer 2004;90: 1022-1024. Cerca con Google

9. Hodgson JT, McElvenny DM, Darnton AJ, Price MJ, Peto J. The expected burden of mesothelioma mortality in Great Britain from 2002 to 2050. Br J Cancer 2005;92: 587-593. Cerca con Google

10. Maltoni C, Minardi F. Recent results of carcinogenicity bioassays of fibres and other particulate materials. IARC Sci Publ 1989: 46-53. Cerca con Google

11. Yarborough CM. The risk of mesothelioma from exposure to chrysotile asbestos. Curr Opin Pulm Med 2007;13: 334-338. Cerca con Google

12. Choe N, Tanaka S, Xia W, Hemenway DR, Roggli VL, Kagan E. Pleural macrophage recruitment and activation in asbestos-induced pleural injury. Environ Health Perspect 1997;105 Suppl 5: 1257-1260. Cerca con Google

13. Zanella CL, Posada J, Tritton TR, Mossman BT. Asbestos causes stimulation of the extracellular signal-regulated kinase 1 mitogen-activated protein kinase cascade after phosphorylation of the epidermal growth factor receptor. Cancer Res 1996;56: 5334-5338. Cerca con Google

14. Weiner SJ, Neragi-Miandoab S. Pathogenesis of malignant pleural mesothelioma and the role of environmental and genetic factors. J Cancer Res Clin Oncol 2009;135: 15-27. Cerca con Google

15. Lee AY, Raz DJ, He B, Jablons DM. Update on the molecular biology of malignant mesothelioma. Cancer 2007;109: 1454-1461. Cerca con Google

16. Bianchi AB, Mitsunaga SI, Cheng JQ, Klein WM, Jhanwar SC, Seizinger B, Kley N, Klein-Szanto AJ, Testa JR. High frequency of inactivating mutations in the neurofibromatosis type 2 gene (NF2) in primary malignant mesotheliomas. Proc Natl Acad Sci U S A 1995;92: 10854-10858. Cerca con Google

17. Sekido Y, Pass HI, Bader S, Mew DJ, Christman MF, Gazdar AF, Minna JD. Neurofibromatosis type 2 (NF2) gene is somatically mutated in mesothelioma but not in lung cancer. Cancer Res 1995;55: 1227-1231. Cerca con Google

18. Deguen B, Goutebroze L, Giovannini M, Boisson C, van der Neut R, Jaurand MC, Thomas G. Heterogeneity of mesothelioma cell lines as defined by altered genomic structure and expression of the NF2 gene. Int J Cancer 1998;77: 554-560. Cerca con Google

19. Fleury-Feith J, Lecomte C, Renier A, Matrat M, Kheuang L, Abramowski V, Levy F, Janin A, Giovannini M, Jaurand MC. Hemizygosity of Nf2 is associated with increased susceptibility to asbestos-induced peritoneal tumours. Oncogene 2003;22: 3799-3805. Cerca con Google

20. Stahel RA F-BE, Opitz I, Weder W. Malignant Pleural Mesothelioma. Future Oncol 2009;5: 391-402. Cerca con Google

21. Soini Y, Kinnula V, Kaarteenaho-Wiik R, Kurttila E, Linnainmaa K, Paakko P. Apoptosis and expression of apoptosis regulating proteins bcl-2, mcl-1, bcl-X, and bax in malignant mesothelioma. Clin Cancer Res 1999;5: 3508-3515. Cerca con Google

22. Attanoos RL, Griffin A, Gibbs AR. The use of immunohistochemistry in distinguishing reactive from neoplastic mesothelium. A novel use for desmin and comparative evaluation with epithelial membrane antigen, p53, platelet-derived growth factor-receptor, P-glycoprotein and Bcl-2. Histopathology 2003;43: 231-238. Cerca con Google

23. Hopkins-Donaldson S, Cathomas R, Simoes-Wust AP, Kurtz S, Belyanskaya L, Stahel RA, Zangemeister-Wittke U. Induction of apoptosis and chemosensitization of mesothelioma cells by Bcl-2 and Bcl-xL antisense treatment. Int J Cancer 2003;106: 160-166. Cerca con Google

24. Travis W. Pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon, France: IARC Press. 2004: World Health Organization Classification of Tumours. Cerca con Google

25. Steele JP. Prognostic factors for mesothelioma. Hematol Oncol Clin North Am 2005;19: 1041-1052, vi. Cerca con Google

26. Spaggiari L, Marulli G, Bovolato P, Alloisio M, Pagan V, Oliaro A, Ratto GB, Facciolo F, Sacco R, Brambilla D, Maisonneuve P, Mucilli F, Alessandrini G, Leoncini G, Ruffini E, Fontana P, Infante M, Pariscenti GL, Casiraghi M, Rea F. Extrapleural pneumonectomy for malignant mesothelioma: an Italian multicenter retrospective study. Ann Thorac Surg 2014;97: 1859-1865. Cerca con Google

27. Scherpereel A, Astoul P, Baas P, Berghmans T, Clayson H, de Vuyst P, Dienemann H, Galateau-Salle F, Hennequin C, Hillerdal G, Le Pechoux C, Mutti L, Pairon JC, Stahel R, van Houtte P, van Meerbeeck J, Waller D, Weder W. Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for management of Malignant Pleural Mesothelioma. Eur Respir J 2009. Cerca con Google

28. Pasello G, Ceresoli GL, Favaretto A. An overview of neoadjuvant chemotherapy in the multimodality treatment of malignant pleural mesothelioma. Cancer Treat Rev 2013;39: 10-17. Cerca con Google

29. Treasure T, Lang-Lazdunski L, Waller D, Bliss JM, Tan C, Entwisle J, Snee M, O'Brien M, Thomas G, Senan S, O'Byrne K, Kilburn LS, Spicer J, Landau D, Edwards J, Coombes G, Darlison L, Peto J, trialists M. Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study. Lancet Oncol 2011;12: 763-772. Cerca con Google

30. Castagneto B, Botta M, Aitini E, Spigno F, Degiovanni D, Alabiso O, Serra M, Muzio A, Carbone R, Buosi R, Galbusera V, Piccolini E, Giaretto L, Rebella L, Mencoboni M. Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma (MPM). Ann Oncol 2008;19: 370-373. Cerca con Google

31. Ceresoli GL, Castagneto B, Zucali PA, Favaretto A, Mencoboni M, Grossi F, Cortinovis D, Del Conte G, Ceribelli A, Bearz A, Salamina S, De Vincenzo F, Cappuzzo F, Marangolo M, Torri V, Santoro A. Pemetrexed plus carboplatin in elderly patients with malignant pleural mesothelioma: combined analysis of two phase II trials. Br J Cancer 2008;99: 51-56. Cerca con Google

32. Ceresoli GL, Zucali PA, Favaretto AG, Grossi F, Bidoli P, Del Conte G, Ceribelli A, Bearz A, Morenghi E, Cavina R, Marangolo M, Parra HJ, Santoro A. Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. J Clin Oncol 2006;24: 1443-1448. Cerca con Google

33. Pasello G, Favaretto A. Molecular targets in malignant pleural mesothelioma treatment. Curr Drug Targets 2009;10: 1235-1244. Cerca con Google

34. LeBlanc HN, Ashkenazi A. Apo2L/TRAIL and its death and decoy receptors. Cell Death Differ 2003;10: 66-75. Cerca con Google

35. Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM. An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science 1997;277: 815-818. Cerca con Google

36. Pan G, O'Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, Dixit VM. The receptor for the cytotoxic ligand TRAIL. Science 1997;276: 111-113. Cerca con Google

37. Marsters SA, Sheridan JP, Pitti RM, Huang A, Skubatch M, Baldwin D, Yuan J, Gurney A, Goddard AD, Godowski P, Ashkenazi A. A novel receptor for Apo2L/TRAIL contains a truncated death domain. Curr Biol 1997;7: 1003-1006. Cerca con Google

38. Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D, Ramakrishnan L, Gray CL, Baker K, Wood WI, Goddard AD, Godowski P, Ashkenazi A. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 1997;277: 818-821. Cerca con Google

39. Emery JG, McDonnell P, Burke MB, Deen KC, Lyn S, Silverman C, Dul E, Appelbaum ER, Eichman C, DiPrinzio R, Dodds RA, James IE, Rosenberg M, Lee JC, Young PR. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 1998;273: 14363-14367. Cerca con Google

40. Gura T. How TRAIL kills cancer cells, but not normal cells. Science 1997;277: 768. Cerca con Google

41. Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer 2002;2: 420-430. Cerca con Google

42. Zhang L, Fang B. Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Ther 2005;12: 228-237. Cerca con Google

43. Gonzalvez F, Ashkenazi A. New insights into apoptosis signaling by Apo2L/TRAIL. Oncogene 2010;29: 4752-4765. Cerca con Google

44. Nagane M, Pan G, Weddle JJ, Dixit VM, Cavenee WK, Huang HJ. Increased death receptor 5 expression by chemotherapeutic agents in human gliomas causes synergistic cytotoxicity with tumor necrosis factor-related apoptosis-inducing ligand in vitro and in vivo. Cancer Res 2000;60: 847-853. Cerca con Google

45. Gibson SB, Oyer R, Spalding AC, Anderson SM, Johnson GL. Increased expression of death receptors 4 and 5 synergizes the apoptosis response to combined treatment with etoposide and TRAIL. Mol Cell Biol 2000;20: 205-212. Cerca con Google

46. Chinnaiyan AM, Prasad U, Shankar S, Hamstra DA, Shanaiah M, Chenevert TL, Ross BD, Rehemtulla A. Combined effect of tumor necrosis factor-related apoptosis-inducing ligand and ionizing radiation in breast cancer therapy. Proc Natl Acad Sci U S A 2000;97: 1754-1759. Cerca con Google

47. Pukac L, Kanakaraj P, Humphreys R, Alderson R, Bloom M, Sung C, Riccobene T, Johnson R, Fiscella M, Mahoney A, Carrell J, Boyd E, Yao XT, Zhang L, Zhong L, von Kerczek A, Shepard L, Vaughan T, Edwards B, Dobson C, Salcedo T, Albert V. HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo. Br J Cancer 2005;92: 1430-1441. Cerca con Google

48. Georgakis GV, Li Y, Humphreys R, Andreeff M, O'Brien S, Younes M, Carbone A, Albert V, Younes A. Activity of selective fully human agonistic antibodies to the TRAIL death receptors TRAIL-R1 and TRAIL-R2 in primary and cultured lymphoma cells: induction of apoptosis and enhancement of doxorubicin- and bortezomib-induced cell death. Br J Haematol 2005;130: 501-510. Cerca con Google

49. Belyanskaya LL, Marti TM, Hopkins-Donaldson S, Kurtz S, Felley-Bosco E, Stahel RA. Human agonistic TRAIL receptor antibodies Mapatumumab and Lexatumumab induce apoptosis in malignant mesothelioma and act synergistically with cisplatin. Mol Cancer 2007;6: 66. Cerca con Google

50. Ashkenazi A, Holland P, Eckhardt SG. Ligand-based targeting of apoptosis in cancer: the potential of recombinant human apoptosis ligand 2/Tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL). J Clin Oncol 2008;26: 3621-3630. Cerca con Google

51. Herbst RS, Eckhardt SG, Kurzrock R, Ebbinghaus S, O'Dwyer PJ, Gordon MS, Novotny W, Goldwasser MA, Tohnya TM, Lum BL, Ashkenazi A, Jubb AM, Mendelson DS. Phase I dose-escalation study of recombinant human Apo2L/TRAIL, a dual proapoptotic receptor agonist, in patients with advanced cancer. J Clin Oncol 2010;28: 2839-2846. Cerca con Google

52. Soria JC, Smit E, Khayat D, Besse B, Yang X, Hsu CP, Reese D, Wiezorek J, Blackhall F. Phase 1b study of dulanermin (recombinant human Apo2L/TRAIL) in combination with paclitaxel, carboplatin, and bevacizumab in patients with advanced non-squamous non-small-cell lung cancer. J Clin Oncol 2010;28: 1527-1533. Cerca con Google

53. Duiker EW, Mom CH, de Jong S, Willemse PH, Gietema JA, van der Zee AG, de Vries EG. The clinical trail of TRAIL. Eur J Cancer 2006;42: 2233-2240. Cerca con Google

54. Kelley SK, Harris LA, Xie D, Deforge L, Totpal K, Bussiere J, Fox JA. Preclinical studies to predict the disposition of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand in humans: characterization of in vivo efficacy, pharmacokinetics, and safety. J Pharmacol Exp Ther 2001;299: 31-38. Cerca con Google

55. Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, Blackie C, Chang L, McMurtrey AE, Hebert A, DeForge L, Koumenis IL, Lewis D, Harris L, Bussiere J, Koeppen H, Shahrokh Z, Schwall RH. Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest 1999;104: 155-162. Cerca con Google

56. Hylander BL, Pitoniak R, Penetrante RB, Gibbs JF, Oktay D, Cheng J, Repasky EA. The anti-tumor effect of Apo2L/TRAIL on patient pancreatic adenocarcinomas grown as xenografts in SCID mice. J Transl Med 2005;3: 22. Cerca con Google

57. Jin H, Yang R, Fong S, Totpal K, Lawrence D, Zheng Z, Ross J, Koeppen H, Schwall R, Ashkenazi A. Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand cooperates with chemotherapy to inhibit orthotopic lung tumor growth and improve survival. Cancer Res 2004;64: 4900-4905. Cerca con Google

58. Soria JC, Mark Z, Zatloukal P, Szima B, Albert I, Juhasz E, Pujol JL, Kozielski J, Baker N, Smethurst D, Hei YJ, Ashkenazi A, Stern H, Amler L, Pan Y, Blackhall F. Randomized phase II study of dulanermin in combination with paclitaxel, carboplatin, and bevacizumab in advanced non-small-cell lung cancer. J Clin Oncol 2011;29: 4442-4451. Cerca con Google

59. Kim KU, Wilson SM, Abayasiriwardana KS, Collins R, Fjellbirkeland L, Xu Z, Jablons DM, Nishimura SL, Broaddus VC. A novel in vitro model of human mesothelioma for studying tumor biology and apoptotic resistance. Am J Respir Cell Mol Biol 2005;33: 541-548. Cerca con Google

60. Liu Q, El-Deiry WS, Gazitt Y. Additive effect of Apo2L/TRAIL and Adeno-p53 in the induction of apoptosis in myeloma cell lines. Exp Hematol 2001;29: 962-970. Cerca con Google

61. Tomasetti M, Rippo MR, Alleva R, Moretti S, Andera L, Neuzil J, Procopio A. Alpha-tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells. Br J Cancer 2004;90: 1644-1653. Cerca con Google

62. Zhao J, Lu Y, Shen HM. Targeting p53 as a therapeutic strategy in sensitizing TRAIL-induced apoptosis in cancer cells. Cancer Lett 2012;314: 8-23. Cerca con Google

63. Mor O, Yaron P, Huszar M, Yellin A, Jakobovitz O, Brok-Simoni F, Rechavi G, Reichert N. Absence of p53 mutations in malignant mesotheliomas. Am J Respir Cell Mol Biol 1997;16: 9-13. Cerca con Google

64. Momand J, Zambetti GP, Olson DC, George D, Levine AJ. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 1992;69: 1237-1245. Cerca con Google

65. Biderman L, Manley JL, Prives C. Mdm2 and MdmX as Regulators of Gene Expression. Genes Cancer 2012;3: 264-273. Cerca con Google

66. Hoe KK, Verma CS, Lane DP. Drugging the p53 pathway: understanding the route to clinical efficacy. Nat Rev Drug Discov 2014;13: 217-236. Cerca con Google

67. Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature 2000;408: 307-310. Cerca con Google

68. Wade M, Li YC, Wahl GM. MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer 2013;13: 83-96. Cerca con Google

69. Toledo F, Wahl GM. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer 2006;6: 909-923. Cerca con Google

70. Bartel F, Schulz J, Bohnke A, Blumke K, Kappler M, Bache M, Schmidt H, Wurl P, Taubert H, Hauptmann S. Significance of HDMX-S (or MDM4) mRNA splice variant overexpression and HDMX gene amplification on primary soft tissue sarcoma prognosis. Int J Cancer 2005;117: 469-475. Cerca con Google

71. Toguchida J, Yamaguchi T, Dayton SH, Beauchamp RL, Herrera GE, Ishizaki K, Yamamuro T, Meyers PA, Little JB, Sasaki MS, et al. Prevalence and spectrum of germline mutations of the p53 gene among patients with sarcoma. N Engl J Med 1992;326: 1301-1308. Cerca con Google

72. Maelandsmo GM, Berner JM, Florenes VA, Forus A, Hovig E, Fodstad O, Myklebost O. Homozygous deletion frequency and expression levels of the CDKN2 gene in human sarcomas--relationship to amplification and mRNA levels of CDK4 and CCND1. Br J Cancer 1995;72: 393-398. Cerca con Google

73. Ito M, Barys L, O'Reilly T, Young S, Gorbatcheva B, Monahan J, Zumstein-Mecker S, Choong PF, Dickinson I, Crowe P, Hemmings C, Desai J, Thomas DM, Lisztwan J. Comprehensive mapping of p53 pathway alterations reveals an apparent role for both SNP309 and MDM2 amplification in sarcomagenesis. Clin Cancer Res 2011;17: 416-426. Cerca con Google

74. Gilkes DM, Pan Y, Coppola D, Yeatman T, Reuther GW, Chen J. Regulation of MDMX expression by mitogenic signaling. Mol Cell Biol 2008;28: 1999-2010. Cerca con Google

75. Gembarska A, Luciani F, Fedele C, Russell EA, Dewaele M, Villar S, Zwolinska A, Haupt S, de Lange J, Yip D, Goydos J, Haigh JJ, Haupt Y, Larue L, Jochemsen A, Shi H, Moriceau G, Lo RS, Ghanem G, Shackleton M, Bernal F, Marine JC. MDM4 is a key therapeutic target in cutaneous melanoma. Nat Med 2012;18: 1239-1247. Cerca con Google

76. McEvoy J, Ulyanov A, Brennan R, Wu G, Pounds S, Zhang J, Dyer MA. Analysis of MDM2 and MDM4 single nucleotide polymorphisms, mRNA splicing and protein expression in retinoblastoma. PLoS One 2012;7: e42739. Cerca con Google

77. Fahraeus R, Olivares-Illana V. MDM2's social network. Oncogene 2013. Cerca con Google

78. Onel K, Cordon-Cardo C. MDM2 and prognosis. Mol Cancer Res 2004;2: 1-8. Cerca con Google

79. Tagawa M, Tada Y, Shimada H, Hiroshima K. Gene therapy for malignant mesothelioma: current prospects and challenges. Cancer Gene Ther 2013;20: 150-156. Cerca con Google

80. Iwakuma T, Lozano G. MDM2, an introduction. Mol Cancer Res 2003;1: 993-1000. Cerca con Google

81. Sekido Y. Molecular pathogenesis of malignant mesothelioma. Carcinogenesis 2013;34: 1413-1419. Cerca con Google

82. Hopkins-Donaldson S, Belyanskaya LL, Simoes-Wust AP, Sigrist B, Kurtz S, Zangemeister-Wittke U, Stahel R. p53-induced apoptosis occurs in the absence of p14(ARF) in malignant pleural mesothelioma. Neoplasia 2006;8: 551-559. Cerca con Google

83. Yang CT, You L, Yeh CC, Chang JW, Zhang F, McCormick F, Jablons DM. Adenovirus-mediated p14(ARF) gene transfer in human mesothelioma cells. J Natl Cancer Inst 2000;92: 636-641. Cerca con Google

84. Vu B, Wovkulich P, Pizzolato G, Lovey A, Ding Q, Jiang N, Liu JJ, Zhao C, Glenn K, Wen Y, Tovar C, Packman K, Vassilev L, Graves B. Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development. ACS Med Chem Lett 2013;4: 466-469. Cerca con Google

85. Tovar C, Graves B, Packman K, Filipovic Z, Higgins B, Xia M, Tardell C, Garrido R, Lee E, Kolinsky K, To KH, Linn M, Podlaski F, Wovkulich P, Vu B, Vassilev LT. MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models. Cancer Res 2013;73: 2587-2597. Cerca con Google

86. Ohta Y, Shridhar V, Bright RK, Kalemkerian GP, Du W, Carbone M, Watanabe Y, Pass HI. VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours. Br J Cancer 1999;81: 54-61. Cerca con Google

87. Demirag F, Unsal E, Yilmaz A, Caglar A. Prognostic significance of vascular endothelial growth factor, tumor necrosis, and mitotic activity index in malignant pleural mesothelioma. Chest 2005;128: 3382-3387. Cerca con Google

88. Strizzi L, Catalano A, Vianale G, Orecchia S, Casalini A, Tassi G, Puntoni R, Mutti L, Procopio A. Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma. J Pathol 2001;193: 468-475. Cerca con Google

89. Masood R, Kundra A, Zhu S, Xia G, Scalia P, Smith DL, Gill PS. Malignant mesothelioma growth inhibition by agents that target the VEGF and VEGF-C autocrine loops. Int J Cancer 2003;104: 603-610. Cerca con Google

90. Ceresoli GL, Zucali, P., Mencoboni, M., De Vincenzo, F., Botta, M., Grossi, F., Bidoli, P., Bajetta, E., Ardizzoni, A., Favaretto, A., Simonelli, M., Lorenzi, E., Gianoncelli, L., Chiti, A., Santoro, A. Phase II study of the combination of bevacizumab plus pemetrexed and carboplatin as first-line therapy in patients with malignant pleural mesothelioma (MPM). 10th International Conference of the International Mesothelioma Interest Group Abstract Book 2010: S06-03. Cerca con Google

91. Dowell J, Taub, R., Lan, C., Xie, Y., Dunphy, F., Blake, V., Kindler, H. A multicenter phase II study of pemetrexed (P), cisplatin (C), and bevacizumab (B) in patients (pts) with advanced malignant mesothelioma (MM). J Clin Oncol 2009;27: 7578. Cerca con Google

92. Kindler HL, Karrison TG, Gandara DR, Lu C, Krug LM, Stevenson JP, Janne PA, Quinn DI, Koczywas MN, Brahmer JR, Albain KS, Taber DA, Armato SG, 3rd, Vogelzang NJ, Chen HX, Stadler WM, Vokes EE. Multicenter, double-blind, placebo-controlled, randomized phase II trial of gemcitabine/cisplatin plus bevacizumab or placebo in patients with malignant mesothelioma. J Clin Oncol 2012;30: 2509-2515. Cerca con Google

93. Ceresoli GL, Zucali PA, Mencoboni M, Botta M, Grossi F, Cortinovis D, Zilembo N, Ripa C, Tiseo M, Favaretto AG, Soto-Parra H, De Vincenzo F, Bruzzone A, Lorenzi E, Gianoncelli L, Ercoli B, Giordano L, Santoro A. Phase II study of pemetrexed and carboplatin plus bevacizumab as first-line therapy in malignant pleural mesothelioma. Br J Cancer 2013;109: 552-558. Cerca con Google

94. Roudier E, Forn P, Perry ME, Birot O. Murine double minute-2 expression is required for capillary maintenance and exercise-induced angiogenesis in skeletal muscle. FASEB J 2012;26: 4530-4539. Cerca con Google

95. Carroll VA, Ashcroft M. Regulation of angiogenic factors by HDM2 in renal cell carcinoma. Cancer Res 2008;68: 545-552. Cerca con Google

96. LaRusch GA, Jackson MW, Dunbar JD, Warren RS, Donner DB, Mayo LD. Nutlin3 blocks vascular endothelial growth factor induction by preventing the interaction between hypoxia inducible factor 1alpha and Hdm2. Cancer Res 2007;67: 450-454. Cerca con Google

97. Zhou S, Liu L, Li H, Eilers G, Kuang Y, Shi S, Yan Z, Li X, Corson JM, Meng F, Zhou H, Sheng Q, Fletcher JA, Ou WB. Multipoint targeting of the PI3K/mTOR pathway in mesothelioma. Br J Cancer 2014;110: 2479-2488. Cerca con Google

98. Xiong J, Yang Q, Li J, Zhou S. Effects of MDM2 inhibitors on vascular endothelial growth factor-mediated tumor angiogenesis in human breast cancer. Angiogenesis 2014;17: 37-50. Cerca con Google

99. Kay BP, Hsu CP, Lu JF, Sun YN, Bai S, Xin Y, D'Argenio DZ. Intracellular-signaling tumor-regression modeling of the pro-apoptotic receptor agonists dulanermin and conatumumab. J Pharmacokinet Pharmacodyn 2012;39: 577-590. Cerca con Google

100. Pasello G, Urso L, Silic-Benussi M, Schiavon M, Cavallari I, Marulli G, Nannini N, Rea F, Ciminale V, Favaretto A. Synergistic antitumor activity of recombinant human Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in combination with carboplatin and pemetrexed in malignant pleural mesothelioma. J Thorac Oncol 2014;9: 1008-1017. Cerca con Google

101. Zucali PA, Ceresoli GL, Garassino I, De Vincenzo F, Cavina R, Campagnoli E, Cappuzzo F, Salamina S, Soto Parra HJ, Santoro A. Gemcitabine and vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma. Cancer 2008;112: 1555-1561. Cerca con Google

102. Xanthopoulos A, Bauer TT, Blum TG, Kollmeier J, Schonfeld N, Serke M. Gemcitabine combined with oxaliplatin in pretreated patients with malignant pleural mesothelioma: an observational study. J Occup Med Toxicol 2008;3: 34. Cerca con Google

103. Pasello G, Nicotra S, Marulli G, Rea F, Bonanno L, Carli P, Magro C, Jirillo A, Favaretto A. Platinum-based doublet chemotherapy in pre-treated malignant pleural mesothelioma (MPM) patients: a mono-institutional experience. Lung Cancer 2011;73: 351-355. Cerca con Google

104. Ceresoli GL, Zucali PA, De Vincenzo F, Gianoncelli L, Simonelli M, Lorenzi E, Ripa C, Giordano L, Santoro A. Retreatment with pemetrexed-based chemotherapy in patients with malignant pleural mesothelioma. Lung Cancer 2011;72: 73-77. Cerca con Google

105. Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem 1996;271: 12687-12690. Cerca con Google

106. Abayasiriwardana KS, Barbone D, Kim KU, Vivo C, Lee KK, Dansen TB, Hunt AE, Evan GI, Broaddus VC. Malignant mesothelioma cells are rapidly sensitized to TRAIL-induced apoptosis by low-dose anisomycin via Bim. Mol Cancer Ther 2007;6: 2766-2776. Cerca con Google

107. Symanowski J, Vogelzang N, Zawel L, Atadja P, Pass H, Sharma S. A histone deacetylase inhibitor LBH589 downregulates XIAP in mesothelioma cell lines which is likely responsible for increased apoptosis with TRAIL. J Thorac Oncol 2009;4: 149-160. Cerca con Google

108. Yuan BZ, Chapman J, Ding M, Wang J, Jiang B, Rojanasakul Y, Reynolds SH. TRAIL and proteasome inhibitors combination induces a robust apoptosis in human malignant pleural mesothelioma cells through Mcl-1 and Akt protein cleavages. BMC Cancer 2013;13: 140. Cerca con Google

109. Rippo MR, Moretti S, Vescovi S, Tomasetti M, Orecchia S, Amici G, Catalano A, Procopio A. FLIP overexpression inhibits death receptor-induced apoptosis in malignant mesothelial cells. Oncogene 2004;23: 7753-7760. Cerca con Google

110. Hoffman WH, Biade S, Zilfou JT, Chen J, Murphy M. Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. J Biol Chem 2002;277: 3247-3257. Cerca con Google

111. Lo Iacono Marco NS, Grosso Federica, Vattarano Simona, Righi Luisella, Papotti Mauro, Bironzo Paolo, Monica Valentina, Scagliotti Giorgio V. Next generation sequencing in malignant pleural mesothelioma: preliminary data from a retrospective cohort of 123 patients. Journal Of Thoracic Oncology 2013;8: S223. Cerca con Google

112. Hori T, Kondo T, Kanamori M, Tabuchi Y, Ogawa R, Zhao QL, Ahmed K, Yasuda T, Seki S, Suzuki K, Kimura T. Nutlin-3 enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through up-regulation of death receptor 5 (DR5) in human sarcoma HOS cells and human colon cancer HCT116 cells. Cancer Lett 2010;287: 98-108. Cerca con Google

113. Kadota K, Suzuki K, Colovos C, Sima CS, Rusch VW, Travis WD, Adusumilli PS. A nuclear grading system is a strong predictor of survival in epitheloid diffuse malignant pleural mesothelioma. Mod Pathol 2012;25: 260-271. Cerca con Google

114. Husai AN AV, Gallan A, McGregor S, Arif Q, Hadi, D, Alikhan MB, Vigneswaran W and Krausz T. Necrosis and nuclear grade are predictors of overall survival in pleural epithelioid malignant mesotheliomas (MM). International Mesothelioma Interest Group (IMIG) Conference abstract book 2014. Cerca con Google

Download statistics

Solo per lo Staff dell Archivio: Modifica questo record