Development of new Pt-based ROS storm inducing polymers with tumor specific toxicity

About This Grant

Abstract Breast cancer is the second leading cause of cancer-related death of women in the United States, and triple negative breast cancer (TNBC) is the most aggressive subtype. It comes back early, spreads fast, has a poor prognosis, and there are limited treatment options. Almost 90% of patients with TNBC that have spread to other parts of the body will pass away within five years, which is a lot worse compared to other subtypes, and the lungs are the most common site for TNBC to spread. Current standard therapies including platinum (Pt) drugs, taxanes, and anthracyclines are widely used but often cause severe toxicity and rapid drug resistance. TNBC responses moderately to current immunotherapies, and the overall treatment effects are heavily affected by a group of immune cells in tumor tissues, the immune-suppressing myeloid cells. This population contributes to forming immune environment which promotes tumor growth by inhibiting immune surveillance. Therefore, novel approaches are urgently needed to help these patients live longer, particularly for TNBC that spreads to distant organs such as the lungs, since they are more frequent and deadly. Reactive oxygen species (ROS) are unstable molecules within cells. While high levels of ROS can be harmful to cancer cells, they also significantly affect the behavior and interaction of cancer cells and myeloid cells in tumors. This makes them a promising target for TNBC treatment. However, most of current drugs do not produce sufficient ROS. Mild ROS not only fail to kill tumor cells but can promote tumor growth. Moreover, the immunosuppression effect remains a critical concern. It is important to design new drugs with high potency of ROS production. Accordingly, we have developed novel Pt-based therapeutics that produce robust ROS production, effectively eradicates TNBC cells rapidly, and successfully suppressed tumor growth in animal models. The goal of this project is to investigate the activities and biological mechanisms of these new drugs on both cancer and immune cells, with a special focus on TNBCs that have spread to lung. We will study the mechanisms how the drugs kill TNBC cells and assess the effectiveness when combined with current first-line TNBC treatment strategies. Moreover, we will explore their overall impact on the immune environment in lung metastatic TNBC nodules. These findings will provide a novel framework for development and assessment of drug efficacy against TNBC and other cancer types. Specific Aims: Aim 1: Elucidate how the ROS-generating Pt drug affects TNBC cells and immune-inhibiting myeloid cells. Aim 2: Assessment the performance of ROS-generating Pt drug in treating lung-spreading TNBC, along with its impacts on immune response.