Developing novel combination therapies for pancreatic cancer

Pancreatic cancer is an aggressive malignancy, with an global 5-year survival rate of 9%. As the disease is often diagnosed in the later stages, the main treatment option available is chemotherapy. Despite recent advancements, gemcitabine is still regarded as the chemotherapy of choice for pancreatic cancer, however one of the major problems is that pancreatic tumours often develop resistance to this therapy. Therefore, in an attempt to combat this resistance we are investigating a repurposed drug (drug X) to develop novel combination therapies for the treatment of pancreatic cancers. Drug X was originally developed for the treatment of autoimmune disease and is already approved for use in humans, which would greatly reduce the time and cost required to bring any combinations developed to clinical trial. Material and Methods The pancreatic cancer cell lines Panc-1 and Mia PaCa-2 were utilised to test drug X in both 2D and 3D cell culture models. The clonogenic assay was used to assess the cytotoxic effect of drug X as both a monotherapy and in various scheduled combinations. Multicellular tumour spheroids (MTS) were also used to assess cytotoxicity of drug X and combinations in a 3D cell model. Finally, combination index analysis was used to assess the 18780261, 2023, S1, Downloaded from https://febs.onlinelibrary.wiley.com/doi/10.1002/1878-0261.13471 by University Of Strathclyde, Wiley Online Library on [08/07/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Molecular Oncology 17 (Suppl. 1) (2023) 1–597 © 2023 The Authors. Molecular Oncology is published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies 423 synergism of drug X in combination, to determine the feasibility of the combinations. Results and Discussions Preliminary results show that drug X is cytotoxic in both pancreatic cancer cell lines tested in a dose-response manner when given as a monotherapy in 2D cell culture, and following combination index analysis drug X showed synergism in combination with gemcitabine and radiation. However in MTS, it did not reduce Mia PaCa-2 spheroid growth as a monotherapy, suggesting that there is alternative mechanisms of action in the 3D model when compare with 2D cell culture. The combinations developed in 2D culture showed little effect on MTS growth, suggesting alternative dosing or composition of combinations may be required. Conclusion Drug X shows potential as a treatment for pancreatic cancer and shows synergism in combination with gemcitabine and radiation. Further studies are required to fully elucidate the mechanism of action (e.g. apoptosis and DNA damage analysis). Further investigation into the differential activity of the combination in MTS will be required to determine if drug X is an appropriate potential treatment. Additionally the combination therapies will be assessed in vivo using the chick embryo model.