Targeting the Mitochondria to Overcome Resistance to Immune Checkpoint Inhibition in Malignant Pleural Mesothelioma

PROJECT SUMMARY Malignant pleural mesothelioma (MPM) is a cancer caused by exposure to asbestos. Inhaled asbestos fibers become embedded in the lining of the lungs, causing harmful inflammation of the pleura and resulting in MPM. Most patients with MPM die within a year after diagnosis as MPM is quite resistant to therapy. Most patients receive standard chemotherapy with cisplatin/pemetrexed combination which only extends survival by an average of about 11 weeks. Alternative therapies have failed to significantly extend survival until 2021, when the FDA approved the combination of immune checkpoint inhibitors (ICI), nivolumab and ipilimumab, as an alternative first-line treatment for MPM. ICI’s harness a patient’s own immune system to fight MPM cancer cells. ICI’s have extended the life expectancy of some patients by about four months compared to traditional chemotherapy regimens. For patients with tumor limited to one side of the chest, surgical resection with chemotherapy have the longest survivals. Our group recently completed a safety and feasible trial in which we administered ICI then performed surgical removal of the MPM tumor. The patients did particularly well; therefore, we are currently opening a larger trial in which we administer either ICI or chemotherapy and ICI then perform surgery. However, despite the addition of ICIs to treatment options, treatment responses only occur in a subset of patients and long-term outcomes of patients with MPM remain poor regardless of the treatment strategy. Thus, finding novel effective strategies to increase the therapeutic response to ICI is a critically unmet need. A well-known problem with treating cancer is that the cancer cells develop resistance to death when treated with any drug. A part of the cell that is responsible resisting treatment is the mitochondria which acts like the engine by providing all the energy for tumor to grow while protecting it from cell death. In our prior work, we found that a specific protein, Myeloid Cell Leukemia (Mcl-1), attaches to the mitochondria to protect it from death. When we used a drug that blocked Mcl-1 with chemotherapy, the mitochondria no longer prevented tumor cell death and the tumor died. Mcl-1 is extremely unstable resulting in rapid expression and destruction which makes it hard to treat. Therefore, targeting proteins that regulate Mcl-1 may be a clinically effective strategy. In our prior ICI trial, we found that a specific pathway within the mitochondria called the methionine metabolic pathway was increased. A protein in that pathway, Protein Arginine Methyltransferase (PRMT) 5, determines whether Mcl-1 will block cell death. In this proposal, we will study whether targeting PRMT5 or Mcl-1 with drugs will restore the tumor cell’s sensitivity to drug treatment. The long-term goal of this proposal is to attack the mitochondria to overcome therapeutic resistance so patients can beat this disease. This study is highly translational in that we will rapidly perform clinical trials based on these results. The goal of this study is to accelerate the development of more effective therapies to improve the survival of patients with MPM.