Anaplastic thyroid carcinoma: novel therapeutic targets and strategies

Libertini, Silvana (2008) Anaplastic thyroid carcinoma: novel therapeutic targets and strategies. [Tesi di dottorato] (Inedito)

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Abstract

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human malignancies, with a mean survival of only 6 months. Therefore, novel therapeutic approaches are desperately required. - dl1520 is a replication competent adenovirus that, due to lack of a functional E1B-55kD gene, can complete its life cycle solely in tumoural cells. We previously demonstrated that dl1520 efficiently kills ATC cells, but high multiplicity of infection (MOI) are required to obtain a significant antineoplastic effect. One of the major limiting factor in the efficient adenoviral transduction is the presence on cell surface of CAR receptor. Inhibition of the Raf/MEK/ERK pathway up-regulates CAR expression in cancer cells, thus improving adenoviral entry and cell killing by adenoviral mutants. To enhance its oncolytic activity, we decided to combine dl1520 with lovastatin, a drug that, blocking mevalonate synthesis, inhibits Raf/MEK/ERK pathway. However, lovastatin does not up-regulate CAR levels but, acting on viral genes expression, enhances viral replication. Indeed, lovastatin enhances in vitro and in vivo dl1520 effects, thus suggesting its potential role as dl1520 adjuvant in ATC therapy. - A common feature of anaplastic thyroid carcinoma is represented by aneuploidy. Aberrant expression of Aurora B occurs in solid tumours and it is associated with chromosome instability and carcinogenesis. Therefore, Aurora B expression has been evaluated in cell lines and samples from human thyroid carcinoma, showing that its expression paralleles the malignant phenotype. To establish a molecular target for ATC, Aurora B expression has been inhibited by RNAi or a specific inhibitor, showing that Aurora B inhibition blocks cell proliferation and cell survival.

Tipologia di documento:Tesi di dottorato
Parole chiave:Anaplastic thyroid carcinoma
Settori scientifico-disciplinari MIUR:Area 06 Scienze mediche > MED/05 PATOLOGIA CLINICA
Coordinatori della Scuola di dottorato:
Coordinatore del Corso di dottoratoe-mail (se nota)
Vecchio, Giancarlo
Tutor della Scuola di dottorato:
Tutor del Corso di dottoratoe-mail (se nota)
Portella, Giuseppe
Stato del full text:Accessibile
Data:2008
Numero di pagine:101
Istituzione:Università degli Studi di Napoli Federico II
Dipartimento o Struttura:Biologia e Patologia Cellulare e Molecolare
Tipo di tesi:Dottorato
Stato dell'Eprint:Inedito
Denominazione del dottorato:Oncologia ed Endocrinologia Molecolare
Ciclo di dottorato:XX
Numero di sistema:2630
Depositato il:03 Luglio 2008
Ultima modifica:04 Febbraio 2009 09:54

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