Grant: Project Grant

Colorectal cancer (CRC) is the second leading cause of cancer-related death. It is often diagnosed at the advanced stages where metastasis in nearby or distant organs is seen in patients. Patients with metastatic disease make up over 60% of CRC patients. Conventional chemotherapy treatments such as oxaliplatin and irinotecan used in the treatment of metastatic CRC, function by damaging the DNA of cancer cells. Many patients do not benefit from this treatment because their tumors have strong DNA repair systems. Our aim in this project is to develop new drugs that can block DNA repair in CRC, 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 CRC cells as well as in CRC tumors inoculated in animals. In addition, the "hit" inhibitors of DNA repair were found to sensitize CRC cells to DNA damaging chemo and radio therapy. We have also developed nano-carriers of these inhibitors of DNA repair that can direct the inhibitors of DNA repair to CRC tumors. The nano-carries of DNA repair inhibitors have shown to increase the anticancer activity of radiation therapy in CRC tumors in mice. In this project, we would develop second generation of these nanocarriers modified on their surface with molecules that can target CRC cells in metastatic sites and evaluate the activity of these systems in specific sensitization of metastatic CRC to DNA damaging chemo and radiotherapy. The toxicity of combination on normal tissues will also be evaluated. Unrepaired DNA damage can lead to the development of immunogenic tumors by several mechanisms. In this context, we will also investigate the potential of developed nanocarriers of DNA repair inhibitors in the induction of immune response against metastatic CRC. This project can generate knowledge and potentially lead to the development of new therapeutics for the treatment of advanced CRC.