Oncolytic adenovirus dl922-947 targets the DNA damage signaling pathway and enhances the effects of radiation therapy
Abagnale, Antonella (2011) Oncolytic adenovirus dl922-947 targets the DNA damage signaling pathway and enhances the effects of radiation therapy. [Tesi di dottorato] (Inedito)
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Replication selective oncolytic viruses (OVs) are a rapidly expanding therapeutic platform for cancer treatment. OVs are characterized by genetic alterations that ablate critical viral protein functions essential for viral replication in normal cells, but non-essential in tumor cells, thus targeting viral replication to tumor cells. dl1520 was the first oncolytic virus described, and we have demonstrated that dl1520 is effective against anaplastic thyroid carcinoma (ATC) cells and tumor xenografts; its antineoplastic effects are enhanced by paclitaxel, doxorubicin, lovastatin and ionising radiation. We have also shown that the second generation oncolytic adenovirus dl922-947 possesses a greater antitumor effect than dl1520 against ATC cells, and that the anti-VEGF monoclonal antibody, Bevacizumab, increased the effects of dl922-947 by improving viral distribution within the tumor mass. Furthermore, we have also shown that AZD1152, a selective Aurora B kinase inhibitor, negatively affects the growth of anaplastic thyroid carcinoma cells and enhances the effects of oncolytic virus dl922-947. So far, preclinical and clinical studies have clearly shown the antineoplastic potential of oncolytic viruses, at least for local treatment, but have also highlighted the need to find associations that could improve their activity. Association of viruses with specific combinations, not only able to directly kill tumor cells but also to increase viral oncolytic activity, would represent a powerful therapeutic tool for the treatment of human neoplasia, in particular for diseases lacking of effective treatment. The main treatment of ATC consists of irradiation plus chemotherapeutic drugs. In order to identify novel treatment able to enhance the effects of OVs, I have evaluated the effects of ionising radiation in combination with dl922-947, focusing my attention on which type of cell death was activated in the combined treatment. Moreover, I have studied the effects of dl922-947 on the DNA damage response pathway and I have also evaluated the effects of an ATM inhibitor on dl922-947’s activity.
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