Interfering with DNA Damage Signals: Radiosensitizing Prostate Cancer Using Small Peptides

摘要

The major goal of this project is to identify small inhibitory peptides that can interfere with critical DNA damage responsive pathways in order to develop novel therapeutic agents for prostate cancer radiotherapy. During the grant funding period, we have identified two DNA damage responsive pathway targets that can be explored for radiosensitization. We have demonstrated that small peptides containing SMC1 phosphorylation or NBS1-ATM binding sequences can abrogate optimal DNA damage responses in vitro. Further we have shown that these peptides can decrease prostate tumor cell clonogenic survival after radiation, indicating these peptides function as powerful radiosensitizers. In order to test in vivo radiosensitization activities, we generated a series of tumor homing peptides containing these sequences and proved tumor specific targeting of the peptides. Prostate cancer xenograft models have been explored though limited radiosensitization effects have been observed. In addition to in vitro and in vivo studies, we have also elucidated the mechanistic insights of inhibitory peptides. Completion of this project will have significant impact on developing molecular targeted radiosensitizers for prostate cancer treatment.