Fellow: Dr. Matthew Berry
Mentor: Dr. Timothy Fan
Topic: Continuation of 2023 Cli-Sci Fellowship – Combination of PAC-1 compound with radiotherapy for canine cancer

I will conduct additional in vitro mechanistic studies using canine cell lines from a variety of tumor histologies and previously generated PC-3 knock out cell lines. I expect PAC-1 treatment will selectively sensitize canine cancer cells to ionizing radiation, which may be related to diminished DNA damage recognition and repair. I will continue exploration of DNA damage response modulation in gene and protein expression studies. Radiobiologic effects in cell lines treated with and without PAC-1 will be further explored in clonogenic survival assays, apoptosis assessments, and cell cycle analyses. Finally, a pilot experiment utilizing a pre-clinical murine model system will be completed to provide in vivo rationale for combining PAC-1 with radiotherapy. This murine model system will investigate DNA
damage response protein modulation in tumors following oral PAC-1 dosing. Additionally, DNA damage following irradiation (using strontium plesiotherapy in flank tumor models) will be quantified using ùõæùõæH2A.X with and without PAC-1 pre-treatment. I expect in vivo DNA damage response protein modulation will corroborate my in vitro findings and that PAC-1 pre-treatment will increase DNA damage (thus increasing ùõæùõæH2A.X signal) following radiotherapy.