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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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.
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