DEVELOPMENT OF NOVEL COMBINATION STRATEGIES FOR THE TREATMENT OF PANCREATIC CANCER

Abstract

Pancreatic cancer represents the seventh leading cause of cancer mortality globally, and despite the advances in cancer therapy over the last two decades, its prognosis is still poor with the survival rate among patients with pancreatic cancer for five years being less than 5%. This can be attributed to late-stage diagnosis, tumour heterogeneity, early metastasis, high local recurrence risk and resistance to conventional chemotherapy. The current single agent or combination-based therapy approaches for pancreatic cancer have either failed to improve the overall survival or offered a marginal improvement as well as increasing the accompanied adverse events. Therefore, this project investigated, for the first time, novel triple combinations treatment schedules utilising the gold standard current treatment of gemcitabine plus the repurposed tyrosine kinase inhibitors (sunitinib or pazopanib) plus external beam radiation in pancreatic cancer cell lines in vitro and in vivo. We hypothesised that these novel combination strategies would improve anti-tumour efficacy in pancreatic cancer models compared to single or double combination therapies. Our novel combination strategies with lower doses of gemcitabine, sunitinib, and XBR, resulted in greater anticancer efficacy than either treatment alone. The concurrent administration of gemcitabine with sunitinib when administered after radiation (three-treatment schedule 2 combination), showed a synergistic effect and was found to be the most effective combination strategy in our models. Furthermore, our three-treatment combination in an in vivo pancreatic cancer nude mouse xenograft model, was the only combination approach able to shrink the tumours while other treatment strategies only delayed the xenografted pancreatic cancer tumour growth. Of note, all mice in this treatment group were euthanised two days before the end of the experiment (day 18) because of 20% weight loss relative to the initial body weight. Altogether, our findings in this project offer a promising approach for treating pancreatic ductal adenocarcinoma in the clinic. Furthermore, lowering doses of all three agents is warranted to decrease the unfavourable side effects while maintaining anti-tumour activity.