The trouble with conventional cancer therapy is that drug delivery is inefficient, and the toxic drugs used are indiscriminate, inadvertently affecting normal tissues. Replicating viruses, such as adenovirus, which can rapidly multiply in, destroy, and spread through cells, have the potential to overcome these problems - if they can be designed to selectively replicate in tumor cells alone. In this issue (Nature Biotechnology), Murali Ramachandra and co-workers optimize a strategy for killing tumors using a novel type of engineered adenovirus (01/PEME).
The p53 cellular protein normally suppresses abnormal cell proliferation that leads to tumors (essentially acting like an “emergency brake” in cell growth). However, when mutated, p53 loses its ability to block abnormal cell growth; indeed, almost 50% of human cancers contain a p53 mutation. Therefore, to selectively target tumor cells, Ramachandra and colleagues engineered an adenovirus that only replicates in cells that lack functional p53.
In order to replicate after infecting a cell, adenovirus employs the cellular transcription factor, E2F, to activate viral genes for its own DNA synthesis. Ramachandra’s team constructed the virus to express an inhibitor that blocks E2F activity in normal cells, thus preventing viral replication in normal cells. They did this by putting expression of the inhibitor under the control of a promoter that is activated by p53. Thus, in normal cells that contain active p53, the inhibitor is expressed and viral replication is suppressed. Conversely, in cancer cells in which p53 is defective and does not activate the promoter, the inhibitor is not made, allowing viral replication to take place. 01/PEME showed strong preference for replication in tumor cells and also inhibited tumor growth in mice, suggesting the strategy could complement existing chemotherapeutics.
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