combining chemistry and recombining viral genomes to develop next generation viral vectors and replicating lytic cancer therapies
There is a desperate need to identify new classes of drugs and therapeutic modalities that conclusively ablate cancer cells but leave normal cells unharmed. Engineering viruses that hone in on tumor cell receptors and that replicate selectively within the tumor mass (oncolytic viruses) have enormous potential as lytic cancer therapies. The development of 'oncolytic viruses' can be achieved by ex ploiting the profound functional overlap between cancer mutations and adenoviral proteins. In clinical trials, the first prototypes of these agents have demonstrated promising efficacy. The clinical experience and new insights into the molecular mechanisms that drive tumor and viral replication can now be used to develop novel viruses with potent and improved therapeutic properties. Unfortunately, current methodologies to engineer such viruses fall short of this goal. The overall objective of this proposal is to develop and apply two enabling technologies that will have a profound impact on the rapid generation and targeting of therapeutic viruses. In the first aim, we will pioneer a novel application of multi- site recombination that will enable the de novo assembly of viral genomes in vitro from genomic component parts and heterologous elements. This will allow multiple compound modifications and properties to be combined overnight to create new and improved viral vectors. The second aim is to develop a novel, genetically encoded, inducible chemical adapter system that targets infection to multiple cellular receptors. Oncolytic viral therapy has the potential to destroy a tumor mass of unlimited size, but only if the virus crosses the vasculature and infection spreads from one cancer cell to another. The reliance of current adenoviral vectors on a single cellular receptor for their uptake limits their therapeutic potential. Altering the chemistry and binding of viral caps ids so that infection can be specifically targeted to any cell type would be a major breakthrough. We will achieve this by using a known property of the cancer drug rapamycin to dimerize heterologous proteins with FKBP and FRB domains.
Arnold O. Beckman exemplifies the meaning of the word humanitarian. Combined with his unwavering enthusiasm for life, his keen sense of humor and his strong moral and ethical principles, he is a national icon.