Novel strategies to improve mesothelioma therapy

PROJECT SUMMARY Exposure to asbestos fibers is the major risk factor for the development of malignant mesothelioma (MM). We demonstrated that asbestos fibers induce HMGB1 translocation from the nucleus to the cytoplasm, inducing autophagy, a protective mechanism for mesothelial cells survival after asbestos exposure and contributing to malignant transformation. Our findings that autophagy is constitutionally activated in MM cells explains MM chemoresistance. Antidepressant drugs (ADs) were shown to block autophagy and our preliminary data suggested that ADs, well-tolerated drugs, inhibited autophagy in MM cells. Moreover, we discovered that a mitochondrial protein called Mcl-1 blocks chemotherapy-induced apoptosis. Inhibition Mcl-1 increased the effects of chemotherapy five-fold, suggesting that the combination of ADs with Mcl-1 inhibitor may be particularly effective in treating MM. Here we propose to test our hypothesis that autophagy MM growth and chemo-resistance, and that ADs, by inhibiting autophagy, increase the sensitivity of MM to chemo-induced apoptosis, which can be further enhanced by Mcl-1 inhibition. To address this hypothesis, we will examine the following aims: AIM 1: To investigate the mechanisms responsible for the resistance of MM cells to chemotherapy. AIM 2: To investigate whether ADs and the Mcl-1 inhibitor increase the efficacy of chemotherapy in MM in mouse models. AIM 3: To investigate, using biopsies from MM patients, the effects of ADs and the Mcl-1 inhibitor, AZD-5991, on tumor cells and the tumor microenvironment, and assess survival. Our novel and unique reagents and resources will help us understand the specific functions of HMGB1 and the related mechanisms that induce autophagy and facilitate MM progression, which may therefore be the most clinically relevant targets for intervention. Using ADs and the Mcl-1 inhibitor to help sensitize MM to chemotherapy will be extremely translational. This study is of great impact to accelerate the development of more effective therapeutic strategies to improve the prognosis of this devastating malignancy.