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Design of an NF-kB Activation-Coupled Apoptotic Molecule for Prostate Cancer Therapy
Final rept. 1 Jan 2007-30 Jun 2008
GEISINGER CLINIC DANVILLE PA
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This proposal is to establish an effective and selective gene therapy technique for prostate cancer. The main idea is to create an NF-kBCaspase-3 fusion protein, designated as NF-kB activation-coupled apoptotic molecule NACAM, that couples activation of NF-kB to activation of Caspase-3, thus to apoptosis. During the eighteen months, we constructed 32 plasmids for testing the function of NACAM and determined the expression of the plasmids in HEK293 cells. We further tested the function of NACAM by examining the caspase activity of NACAM and interaction of NF-kBCaspase-3 fusion proteins. We found that p65-L-SS and p65-L-LS are capable of forming active caspase-3. However, because NF-kBCaspase-3 fusion proteins form homo-dimers, NF-kBCaspase-3 subunit fusion proteins have only small portion to form NACAM. Nevertheless, our work provided a preliminary study for creating an NF-kB activation-coupled apoptosis molecule. In addition to NACAM, we continued our research on development of mitogenesis-coupled apoptosis molecular device MCAMD. The first-phase research of MCAMD was funded by DOD-PCRP concept award W81XWH-05-1-0178 and completed in June of 2006. Because MCAMD is technically related to NACAM, we further developed MCAMD with this funding support and successfully established MCAMD system in HEK293 cells. We have observed that mitogenic conditions induced cellular apoptosis through MCAMD, providing preliminary data for application of MCAMD to prostate cancer therapy. This work is in preparation of manuscript for publication and in process of application for a patent. Future studies will include a to further characterize and improve NACAM and b to test the function of MCAMD for killing cancer cells in a prostate cancer cell system and a prostate cancer cellxenografted mouse model.
APPROVED FOR PUBLIC RELEASE