Blocking Blood Supply to Breast Carcinoma With a DNA Vaccine Encoding VEGF Receptor-2

摘要

We proved the major hypothesis driving this project that effective regression of breast cancer growth and metastases can be achieved by suppressing tumor angiogenesis with an orally delivered DNA-based vaccine carried by double attenuated Salmonella typhimurium. For this approach, the murine vascular endothelial growth factor receptor-2 (FLK-1) proved to be an effective target. We also targeted the inhibitor of apoptotic protein, surviving, and endoglin and achieved a similar protection against lethal tumor cell challenges. Our data demonstrate that the major mechanism involves MHC- Class I restricted CD8 T cell-mediated killing of proliferating endothelial cells. The use of anti-angiogenic cytokine IL-18 and targeting of tumor- associated macrophages (TAMs) also proved the anti-tumor efficacy of our anti- angiogenic vaccines. We also found that there are no serious the side effects of our DNA vaccines, thus providing the basis for their future clinical application. In fact, the FLK-1 vaccine is in its final preparation for Phase I clinical trials. Our research findings were also adapted by other investigators and extended to therapies of other diseases such as arteriosclerosis. Overall, research funded by this award was successful in providing new strategies for immune therapies of both breast carcinoma and other diseases.