Novel DNA cross-linking agents and combination strategies for tumor-specific activation

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Project summary/abstract Cancer cells are in a state of increased basal oxidative stress due to their aberrant growth. As a result, cancer cells have elevated levels of reactive oxygen species (ROS) compared to normal cells. This feature has been employed to develop a class of ROS-activated prodrugs that only become cytotoxic in the presence of ROS. The effectiveness of ROS-activated prodrugs as monotherapy for cancer faces many challenges, including tumor heterogeneity, insufficient prodrug activation, difficulty in targeted drug delivery, lack of therapeutic durability, etc. Novel strategies are urgently needed to augment the efficacy and selectivity of ROS-activated prodrugs to a wide variety of cancer. The H2O2-activated DNA alkylating agents developed by our group exhibit selective toxicity towards cancer cells under oxidative stress but not normal cells, suggesting their potential usage in combination with reagents or cancer therapies that amplify ROS level specially in cancer cells. It has been reported that prooxidants such as vitC can act as potent pro-oxidants to induce H2O2 specifically in cancer cells while normal cells are protected due to higher Catalase expression that quenches H2O2. The non-toxic feature of the H2O2- activated DNA cross-linking agents developed in our lab, together with the findings showing that vitC selectively intensify H2O2 accumulation in cancer cells, provides a compelling rationale for combining these two therapeutic modalities in a synergistic manner. The overarching hypothesis of this project is that the combination of selected pro-oxidants with ROS-activated prodrugs can achieve synergistic and durable antitumor effects while minimizing unwanted side-effects. Specifically, we will develop novel ROS-activated anticancer prodrugs with improved tumor specificity and drug like property (Aim 1), and identify ROS-activated prodrugs that synergize with pro-oxidants to improve the efficacy of ROS-activated prodrugs (Aim 2). The significance of this project is that targeting tumor redox through the combination of ROS-activated prodrugs and prooxidants represents an effective cancer treatment strategy. The proposed research will identify clinically applicable ROS-activated prodrugs that are compatible with prooxidant to confer efficacious, selective, and durable therapeutic benefits. Successful completion of the project will pave the way for repurposing ROS-activated DNA alkylating agents for cancer treatment.