Grant: Project Grant

Lung cancer is the 2nd most common cancer and the number one cause of cancer related death in North America. Lung cancer is rarely detected at the early stages of the disease because symptoms tend to be mild and non-specific. When diagnosed, 60-75% of patients have advanced disease and are considered incurable. For the large group of patients with advanced disease, survival is only 12-15 months after treatment. Even a small improvement in treatment, is significant for these patients. Lung cancer treatment in patients with advanced disease, is based on damaging the DNA of cancer cells with chemotherapy and radiation. Many patients do not benefit from this treatment because their tumors have strong DNA repair systems. Our aim is to develop new drugs that can block DNA repair in lung cancer, but do not affect normal cells, so that the toxic effects of DNA repair inhibition is not observed in normal cells. We have already found "hit" molecules that block specific DNA repair pathways in human lung cancer cells through chemistry and modelling of their interactions with the DNA repair pathways. The "hit" inhibitors of DNA repair were found to sensitize cancer cells to DNA damaging chemo and radio therapy. In this proposal, we will develop nano-carriers with specific signal molecules on their surfaces that bind to lung tumor cells but not to normal cells. These nano-carriers will direct the inhibitors of DNA repair to lung tumors, so that their activity can be enhanced,. They will also reduce drug exposure to normal cells so that their toxic side effects are reduced. We also propose to make the nanocarriers traceable, so that their accumulation in the tumor cells can be tracked in patients. We propose to hit the tumor cells in the lung with DNA damaging radiation at the time of maximum accumulation of DNA repair inhibitors in the tumor. This strategy is expected to enhance the effect of therapy in cancer elimination while reducing the side effects of treatment.