(M1130-10-58) Drug Repurposing: A Therapeutic Approach to Modulate Immune Microenvironment in Pancreatic Cancer

Purpose: Pancreatic ductal adenocarcinoma (PDAC) has been predicted to be the second leading cause of cancer-related deaths in the USA by 2030. The biology of PDAC is characterized by a complex microenvironment with high desmoplastic surrounding. Due to certain roadblocks such as side effects of standard chemotherapies, development of resistance and low immune infiltration, current therapeutic options are limited. Immunotherapy has shown positive results in various cancers however, to date, it has it majorly failed in PDAC clinical trials. The low infiltration of immune cells has been purported to be a critical factor for this failure. In our current study, through drug repurposing, we identified immunomodulatory effects of an anti-parasitic compound (MB – compound identity hidden due to IP restrictions) in the PDAC tumor microenvironment.

Methods: Various studies were performed to assess the anti-cancer activity of MB in PDAC cell lines. To identify the IC50 values, Sulforhodamine-B cytotoxicity assay was used. To identify the mode of cell death, Annexin/APC assay was used. Further, the anti-cancer effect of MB was confirmed in-vivo using the C57/B6 orthotopic PDAC model wherein a murine PDAC cell line PO2 was injected into the head of the pancreas through surgery. Studies were also performed on human peripheral blood mono-nuclear cells using Flow Cytometry analysis and ELISA assay to study the effect of MB on immune cells in vitro.

Results: We observed a dose-dependent growth suppressive effect of MB on PDAC cell lines MiaPaca-2, HPAC, BxPC3, Panc-1, AsPC-1 and murine PDAC cell line PO2. The IC₅₀ of MB ranged from 4-6 μM. We confirmed apoptosis as the mode of cell death induced by MB in PDAC cell lines and 3-4-fold apoptosis was observed. Further, MB showed an 80% tumor growth suppression in an orthotopic PDAC model in C57/BL6 mice. In the orthotopic model, an interestingly higher infiltration of cytotoxic CD8 T cells within the MB-treated groups was observed as compared to control groups. Co-culture assays using PDAC cells and human PBMCs also showed higher activation of T cells following MB treatment and the results were confirmed using ELISA assay.

Conclusion: The immunomodulatory effect of MB in PDAC is a novel identification and is critical for therapeutic development against PDAC. The failure of immunotherapy in PDAC can be addressed by combining immune checkpoint inhibitors such as anti-PD-1/PD-L1 with immunomodulatory compounds such as MB. This new approach might prove beneficial for reviving the failed immunotherapeutic development against PDAC.

Acknowledgements: The name of the compound used for repurposing in the study cannot be declared since a patent application is still in process.