Abstract 5470: Inhibition of facilitates chromatin transcription complex attenuates mesothelioma growth

Abstract

Abstract Introduction: Malignant pleural mesothelioma (MPM) is an aggressive incurable cancer usually associated with asbestos exposure. MPM has unique molecular features such as wild-type p53 (>90% regardless of histology) and aberrantly activated NF-κB. A diverse spectrum of anti-MPM therapeutic agents have been trialed, but clinically effective ones remain elusive. Herein, we propose to use a novel small molecule (CBL0137) that simultaneously suppresses NF-κB and activates tumor suppressor p53 via targeting FAcilitates Chromatin Transcription (FACT) complex, a histone chaperone critical for DNA repair in cancers. Methods: We employed in-silico, in-vitro and in-vivo MPM models and patient tumor specimens to characterize CBL0137 efficacy in MPM. CBL0137 effects were assessed in a panel of MPM cell lines by proliferation, colony foci formation, flow cytometry, and cell cycle assays. Drug-specific mechanisms were verified at transcript and protein levels using appropriate molecular assays. Both monotherapy and combinatorial regimens were tested to evaluate the optimal deployment of CBL0137 in comparison to several controls including standard chemotherapy. Immunodeficient (NSG) mice with subcutaneous and orthotopic MPM tumor grafts were used to evaluate the anti-tumor efficacy of CBL0137. Kaplan-Meier and log-rank test were applied for survival outcomes. Results: We observed that transcript and protein levels of SSRP1 and SPT16, subunits of the FACT complex, were significantly upregulated in our collection of MPM cell lines and specimens compared to normal. The TCGA database revealed that overexpression of these FACT subunits was associated with poor survival. As determined by western blot and luciferase-reporter assay, CBL0137 simultaneously inhibited NF-κB and activated p53 in MPM cells. CBL0137 treatment significantly (p<0.05) suppressed MPM cells proliferation, invasiveness, colony foci formation, and increased the number of apoptotic cells. Interestingly, in combination with cisplatin, CBL0137 exhibited additive anti-tumor activity in much lower dose ranges compared to monotherapy. Additionally, CBL0137 synergized with different classes of agents like microRNA-215, which triggers activation of p53 via regulation of MDM2 at transcript level. In vivo, CBL0137 treatment significantly suppressed MPM tumor growth in subcutaneous and orthotopic xenograft models compared to control. Kaplan-Meier analysis showed that CBL0137 treatment improved overall survival. Conclusions: MPM is dependent on FACT for tumor progression since higher levels of SSRP1 and SPT16 are associated with worse prognosis. This MPM vulnerability can be leveraged to identify novel therapeutic paradigms. Targeting this MPM dependency by CBL0137 (dual effects on NF-κB and p53) alone or in various combinations with different classes of drugs holds great promise for improved outcomes regardless of histotype. Citation Format: Anand Singh, Nathanael Pruett, Roma Pahwa, Sudheer K. Gara, Shivani Dixit, Agnes Choi, David S. Schrump, Chuong D. Hoang. Inhibition of facilitates chromatin transcription complex attenuates mesothelioma growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5470.