Homo sapiens Transcriptome or Gene expression
Malignant pleural mesothelioma (MPM) is an aggressive therapy-resistant cancer with unique molecular features. Numerous agents have been tested, but clinically effective ones remain elusive. Herein, we propose to use a small molecule CBL0137 (curaxin) that simultaneously suppresses nuclear factor-kB (NF-kB) and activates tumor suppressor p53 via targeting FAcilitates Chromatin Transcription (FACT) complex, a histone chaperone critical for DNA repair. We used MPM cell lines, murine tumor models (both xeno- and allo-grafts), MPM patient samples to characterize anti-tumor effects of CBL0137 and to delineate specific molecular mechanisms. We verified that CBL0137 induced apoptosis and cell cycle arrest. We also discovered that MPM is a FACT-dependent cancer with overexpression of both subunits structure-specific recognition protein 1 (SSRP1), a poor prognosis indicator, and suppressor of Ty16 (SUPT16H). We defined several novel uses of CBL0137 in MPM therapy. In combination with cisplatin, CBL0137 exhibited additive anti-tumor activity compared to monotherapy. Similarly, CBL0137 (systemic) could be combined with other novel agents like microRNA-215 (intrapleural) as a more effective regimen. Importantly, we established that CBL0137 induces immunogenic cell death that contributes to activating immune response pathways in MPM. Therefore, when CBL0137 is combined with dual immune checkpoint inhibitors MPM tumor growth is significantly suppressed. We identified an unrecognized molecular vulnerability of MPM based on FACT dependency. CBL0137 alone and in several combinations with different therapeutics showed promising efficacy, including that of improved anti-tumor immunity. Overall, these preclinical findings suggest that CBL0137 could be ideally suited for use in MPM human trials.