Radiation is an important component of therapy for locally advanced pancreatic cancer as evidenced by its ability to improve both local control and survival as well as by the finding that 1/3 of pancreatic cancer patients die as a result of local disease progression (1-3). Despite the benefits of radiation therapy for pancreatic cancer, further improvements are urgently needed. Radiation kills cells by induction of DNA double strand breaks (DSBs) and repair of these DSBs is a mechanism of tumor cell resistance to radiation (4, 5). Thus, in the current proposal we plan to selectively sensitize pancreatic cancer cells and tumors to radiation by inhibition of DNA repair by the DNAPK inhibitor M3814. We anticipate that M3814 will delay the repair of radiation-induced DSBs resulting in persistent and lethal DNA damage in tumor cells. In addition, we hypothesize that M3814 in combination with radiation will increase innate immunity in tumor cells that will contribute to additional tumor cell lethality.
The overall objective of this study is to evaluate the potential of M3814 as a radiation sensitizer in pancreatic cancer. The findings of this study will form the foundation for a future clinical trial combining M3814 with radiation in locally advanced pancreatic cancer. While this proposal is focused exclusively on the combination of M3814 with radiation, positive results would support future studies extending to chemotherapy and/or immunotherapy combinations.
| Pal, Anupama; Rehemtulla, Alnawaz (2018) Imaging Proteolytic Activities in Mouse Models of Cancer. Methods Mol Biol 1731:247-260 |
| Parsels, Leslie A; Karnak, David; Parsels, Joshua D et al. (2018) PARP1 Trapping and DNA Replication Stress Enhance Radiosensitization with Combined WEE1 and PARP Inhibitors. Mol Cancer Res 16:222-232 |
| Morgan, Meredith A; Canman, Christine E (2018) Replication Stress: An Achilles' Heel of Glioma Cancer Stem-like Cells. Cancer Res 78:6713-6716 |
