We propose to test if protein transduction technology can improve the efficacy of adenoviral gene-therapy vectors for the treatment of cancer. In cell culture experiments, cancer cells can easily be eliminated with cancer targeted adenoviral gene-therapy vectors. However, in mice and humans, inefficient gene transfer remains a hurdle that has been extremely difficult to overcome. A p53-expressing adenoviral vector is in clinical use in China and has been placed on the fast track for FDA approval.
Published data indicate an extremely favorable safety profile, but overall, the therapeutic effect has been limited. Clearly, gene-transfer efficacy of adenoviral vectors has to be improved for more efficient therapy. The basic domain of HIV-1 Tat (a section of a protein made by the HIV virus, also called the protein transduction domain) can enter intact cells and has been used to deliver a wide variety of proteins to many cell types. Tat-fusion proteins, produced in bacteria, purified and then applied to cells, have been studied widely to manipulate cancer biology.
This approach is effective in cell culture experiments, but so far there is only limited evidence for efficacy in mouse tumor models. Very few studies have investigated the potential of the delivery of Tat-fusion proteins with gene therapy vectors. We hypothesize that Tat-fusion peptides expressed at high levels with an adenovirus will result in more effective treatment of solid tumors.
Furthermore, we hypothesize that smaller unfolded peptides fused to Tat will lead to more efficient distribution within tumors, compared to complexly folded large proteins. The delivery of peptides fused to a protein transduction domain with adenoviral vectors is a new approach that could find broad application.
