Grant: CIHR Fellowship

This research projects deals with cancer therapy and how to introduce a new targeted therapy for some types of cancer by making use of their biological characteristics. It is known that tumors often fail to make particular proteins. This is not fatal for the tumor cells and in fact is sometimes the reason that they grow better than normal cells. However if the loss of this protein is combined with the loss or inhibition of another protein, the combination either kills the cancer cells or makes them very sensitive to chemotherapy or radiotherapy. This phenomenon is called synthetic lethality. Because the normal cells produce the first protein, the loss of the second protein is not particularly harmful to them and so if we can find a way to inhibit the second protein only the cancer cells will be killed or weakened. The trick is to identify the synthetic lethal partnerships, especcially those where an inhibitor of the second protein is already available or being developed. Recently, our group identified a chemical that inhibits an important enzyme inside the cell called polynucleotide kinase/phosphatase (PNKP), which is required to mend DNA damaged by radiotherapy and chemotherapy. When we screened to see if PNKP has any possible synthetic lethal partners we identified an important protein called PTEN that is frequently missing or inactive in breast cancer cells. We intend to confirm that the combined loss of PNKP and PTEN does indeed kill or weaken breast cancer cells grown. We will use breast cancer cells grown in dishes and as tumours in mice. We also intend to learn more about the underlying mechanism for synthetic lethality by looking for synthetic lethal partners of another DNA repair protein related to PNKP called DNA polymerase beta. This research is expected to have potential therapeutic value because it targets cancer cells and should leave normal tissue relatively unaffected, which would translate into decreased side effects in the patient.