New Combination Therapies for Advanced Prostate Cancer Based on the Radiosensitizing Potential of 5-Azacytidine

摘要

The research covered under this award is designed to further study our original finding that the drug 5-azacytidine increases the responsiveness of prostate cancer cells and xenografts to radiation. The first aim of our research was to identify molecular targets of 5-azacytidine which mediate its radiation sensitizing effect. We originally hypothesized that 5-azacytidine likely suppresses DNA double-strand (DSB) break repair by modulating the non- homologous end-joining pathway, but found no evidence to support this hypothesis. We did identify two targets of 5-azacytidine, Rad50 and MAP2K6, which may suppress DSB repair by modulating homologous recombination and cell cycle arrest. Based on our latest data, however, we conclude that 5-azacytidine predominantly sensitizes prostate cancer cells to radiation by sensitizing the genomic DNA itself to DNA breakage, rather than by suppressing DSB repair. We are currently investigating whether this direct modulation of DNA integrity has an additive or synergistic combined effect with radiation. The second aim of our research was to verify the effects of a combined triple treatment regimen of 5-azacytidine, flutamide, and radiation on local control of xenografted human-derived prostate tumors. Complete local control was observed for a period of 25 days after an initial 5 day treatment block with a combination of 5- azacytidine, flutamide, and radiation. Although tumor growth was eventually restored, the total time needed for triplication of the tumor was 2x longer than observed for the control and 1.5x longer than observed for the group treated with radiation alone. It must be noted that an initial statistical analysis arbitrarily based on linear regression narrowly failed to show a statistical difference between the triple treatment group and the control group treated with radiation alone.