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Abstract:
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The creation of potent oncolytic viruses (OVs) suitable for the clinic may require new strategies in virus design. Replication-competent viruses facilitate a variety of approaches to achieving tumor specificity. Altered expression of microRNAs is a common hallmark of cancer that this thesis demonstrates can be used to alter expression of a potent wild-type viral gene to achieve tumor-specific replication of an engineered vesicular stomatitis virus (VSV). Incorporation of microRNA complementary sequences (miRTs) within VSV causes reduced accumulation of miRT containing mRNAs. Let-7 miRTs introduced into the 3' untranslated region (3'UTR) of VSV matrix protein mRNA eliminate undesirable replication and associated toxicity in normal cells but permit growth in cancer cells both in vitro and in vivo. Similarly the incorporation of mir34a miRTs results in reduced in vitro VSV replication and cytotoxicity in the presence of activated p53. This thesis provides proof of concept that viruses designed to exploit the differential microRNA expression in cancer cells is a viable approach, potentially useful in optimizing oncolytic viral gene expression for maximal antitumor activity and safety. |
