Colorectal cancer is one of the leading causes of cancer death worldwide, with the liver being the most common and critical site for development of colorectal cancer metastases. Current treatments include surgical resection, a highly invasive procedure. However, less than 10% of patients with liver metastases are appropriate surgical candidates and most patients die within 2 years of being diagnosed with such disseminated disease. Modifications of current treatments are unlikely to significantly influence the natural progression of the disease. Genetic therapy for colorectal cancer is a therapeutic alternative that could provide a less invasive treatment of the disease. Here, we propose to use the Sleeping Beauty (SB) transposon vector system, to provide sustained expression of the transgene, """"""""which is required to halt tumor growth and prevent recurrence of metastatic cancer cell growth.
Four specific aims are proposed.
In Aim 1, Sleeping Beauty transposons containing antiangiogenic and immunostimulatory genes under transcriptional regulation of tumor specific promoters will be assembled and tested for gene expression and transposition in vitro.
In Aim 2, stealth liposome complexes loaded with reporter and antitumor therapeutic transposons will be targeted to tumor cells using a fractalkine receptor peptide amphiphile. These complexes will be tested for their antitumor effectiveness in vitro.
In Aim 3, reporter transposons will be injected intravenously with or without SB transposase into tumor bearing mice, subsequently testing for sustained gene expression in tumor.
In Aim 4, therapeutic transposons along with SB transposase-encoding plasmid will be injected intravenously into tumor bearing mice. Antiangiogenic and immunostimulatory gene expression, duration of expression and inhibitory or suppressive effects on tumor growth will be monitored. These experiments will provide a clinically relevant model for targeted cancer gene therapy. Successful completion of these studies will set the stage for large animal model studies with subsequent development of a clinical trial for treatment of metastatic colorectal cancer by non-viral gene therapy.
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