Adenoviral Vectors for Prodrug Activation-based Gene Therapy for Cancer
Joshua C. Doloff,
David J. Waxman.
Cancer cell heterogeneity is a common feature - both between patients diagnosed with the same cancer and within an
individual patient’s tumor - and leads to widely different response rates to cancer therapies and the potential for the emergence of drug
resistance. Diverse therapeutic approaches have been developed to combat the complexity of cancer, including individual treatment
modalities designed to target tumor heterogeneity. This review discusses adenoviral vectors and how they can be modified to replicate in
a cancer-specific manner and deliver therapeutic genes under multi-tiered regulation to target tumor heterogeneity, including
heterogeneity associated with cancer stem cell-like subpopulations. Strategies that allow for combination of prodrug-activation gene
therapy with a novel replication-conditional, heterogeneous tumor-targeting adenovirus are discussed, as are the benefits of using
adenoviral vectors as tumor-targeting oncolytic vectors. While the anticancer activity of many adenoviral vectors has been well
established in preclinical studies, only limited successes have been achieved in the clinic, indicating a need for further improvements in
activity, specificity, tumor cell delivery and avoidance of immunogenicity.
Keywords: Cancer gene therapy, cytochrome P450 prodrug activation, replication-conditional adenovirus, oncolytic adenovirus, tumor
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