Grant: Operating Grant

Despite major advances in targeted chemotherapy, the major forms of therapy continue to be surgery, radiotherapy and conventional chemotherapy. The main target for radiotherapy, and many conventional drugs, is the cell's DNA. Not surprisingly, the levels of DNA damage and the repair of that damage influence cell survival and affects clinical outcome. As a result, DNA repair systems are emerging as therapeutic targets to enhance cell killing by radiation and chemotherapeutic agents. This proposal focuses on an important DNA repair enzyme, namely polynucleotide kinase/phosphatase (PNKP), which plays a key role in the repair of DNA damage induced by radiation and a broad range of chemical compounds. We have recently identified a chemical (A12B4C3) that inhibits this enzyme and shown that the chemical sensitizes cells to radiation. This proposal is intended to determine the usefulness of targeting PNKP, making use of cells grown in tissue culture and tumour models grown in mice. First, we will examine if treatment with A12B4C3 sensitizes cancer cells to a variety of widely-used chemotherapeutic agents. Second, we will test the ability of A12B4C3 to sensitize cells to radiation under more clinically relevant conditions, taking into account the oxygen status of the cells. Finally, we will examine the potential for A12B4C3 to act as a single agent against cells that lack key proteins shown to be required for cell survival if PNKP is absent. Such preclinical testing of the targeting of PNKP is essential. If the utility of targeting PNKP is confirmed, it will provide a greater impetus to fully develop a drug for clinical use.