Vivek Gupta

Title : Repurposing clofazimine for efficacy in mesothelioma - In-vitro and Ex-vivo evaluation

Abstract:

Aims: Malignant pleural mesothelioma (MPM) is a rare cancer of lungs’ pleural cavity, with minimally effective therapies available. Thus, there exists a necessity for drug repurposing which is an attractive strategy for drug development in MPM. Repurposing of an old FDA-approved anti-leprotic drug, Clofazimine (CFZ), presents an outstanding opportunity to explore its efficacy in treating MPM.

Main methods: Cytotoxicity, scratch assay, and clonogenic assays were employed to determine CFZ’s ability to inhibit cell viability, cell migration, and colony growth. 3D Spheroid cell culture studies were performed to identify tumor growth inhibition potential of CFZ in MSTO-211H cell line. Gene expression analysis was performed using RT-qPCR assays to determine the CFZ’s effect of key genes. Western blot studies were performed to determine CFZ’s ability to induce apoptosis its effect to induce autophagy marker.

Key findings: CFZ showed significant cytotoxicity against both immortalized and primary patient-derived cell lines with IC₅₀ values ranging from 3.4 µM (MSTO-211H) to 7.1 µM (HAY). CFZ significantly impaired MPM cell cloning efficiency, migration, and tumor spheroid formation. 3D Spheroid model showed that CFZ resulted in reduction in spheroid volume. RT-qPCR data showed downregulation of genes β-catenin, BCL-9, and PRDX1; and upregulation of apoptosis markers such as PARP, Cleaved caspase 3, and AXIN2. Additionally, immunoblot analysis showed that CFZ down-regulates the expression of β-catenin (apoptosis induction) and up-regulates p62, LC3B protein II (autophagy inhibition).

Significance: It can be concluded that CFZ could be a promising molecule to repurpose for MPM treatment which needs numerous efforts from further studies.

Audience Take Away Notes:

• Severity and causes of malignant pleural mesothelioma
• Importance of drug repurposing for rare and orphan diseases
• Efficacy of clofazimine in reducing tumor burden from mesothelioma

Biography:

Dr. Vivek Gupta is an Associate Professor, and Associate Dean of Graduate Education & Research at St. John’s University College of Pharmacy. Dr Gupta is an experienced pharmaceutical researcher with interests in developing novel therapies for rare respiratory disorders. His expertise lies in the fields of novel drug discovery and repurposing, and non-invasive delivery of small and macromolecules via inhalation route. Dr. Gupta’s research group has published >75 high-impact studies. Dr. Gupta also serves on editorial boards of many peer-reviewed journals. Multiple technologies and therapies developed by Dr. Gupta’s group have been patented and have been licensed to biotech start-ups including PulmoSIM Therapeutics.