Abstract B56: Paclitaxel-loaded microparticles promote cancer cell death and reduce gemcitabine resistance in a pancreatic cancer cell line

Abstract

Abstract Pancreatic cancer is the fourth leading cause of cancer death in the United States with only 7% of diagnosed patients surviving 5 years. Most pancreatic cancer patients are not surgical candidates due to advanced stage at diagnosis. Current systemic chemotherapies, while exposing patients to the adverse side effects of treatment, have not been very effective at decreasing tumor burden primarily due to poor systemic drug uptake resulting from the dense stromal nature of pancreatic tumors. Poly (lactic-co-glycolic acid)-based microparticles (MPs) are a promising tool for localized drug delivery within the tumor due to their biocompatibility, flexibility in the encapsulation of different drugs and extended drug release inside the tumor. Previous studies in our laboratory with gemcitabine-loaded microparticles (GMPs) showed an enhanced cell killing effect against the PANC-1 and MIAPaCa-2 human pancreatic ductal adenocarcinoma cell lines. In addition, we tested the efficacy of these GMPs by direct injection into established subcutaneous MIAPaCa-2 tumors in nude mice. We observed a significant increase in apoptosis (p<0.05) and a trending decrease in tumor volume in the GMPs-injected MIAPaCa-2 tumors compared to the blank microparticles-injected and control tumors. Paclitaxel (PTX) is an FDA-approved drug to treat pancreatic cancer but the systemic toxicity restricts the dosing and therefore efficacy of the treatment. Recently, a new version of PTX, nab-paclitaxel, has been approved and exhibits increased effectiveness in a proportion of pancreatic cancer patients. It has been described that PTX improves gemcitabine effects, making them an attractive combination for treatment. The present study investigated whether paclitaxel-loaded microparticles (PMPs) in the range of 10-30 microns, as a single agent and in combination with GMPs, are able to promote cell death and overcome the resistance against gemcitabine in vitro. For this study, we used the PANC-1 cell line, which is less sensitive to gemcitabine, to investigate the effect of PMPs on proteins involved in drug resistance by cancer cells prior to and during gemcitabine treatment, as well as potential cell death effects. Using different volumes of PMPs as a single agent, we observed a decrease in ribonucleotide reductase catalytic subunit M1 (RRM1) and in cytidine deaminase (CDA) protein expression, which are known resistance markers for gemcitabine in pancreatic cancer. In addition, cell viability was determined using Trypan Blue exclusion assay and we confirmed that the treatment significantly increased cell death in comparison with the control cells. We also observed an increase in cleaved-caspase 3 expression indicating engagement of the apoptotic cascade. Subsequently, we treated PANC-1 cells with a sequential combination of PMPs first followed by GMPs, and observed an effect of PTX on certain resistance proteins, as well as an increase in cell death when combining the MPs. In conclusion, our data suggests that PMPs could reduce resistance barriers and, combined with GMPs, could enhance cancer cell death. Further studies are needed to investigate PMPs injections into established mouse tumors to confirm efficacy. The described drug delivery method has the potential to be a more efficient local treatment modality than systemic gemcitabine and paclitaxel against pancreatic cancer. Citation Format: Maria Munoz-Sagastibelza, Laura Martello-Rooney.{Authors}. Paclitaxel-loaded microparticles promote cancer cell death and reduce gemcitabine resistance in a pancreatic cancer cell line. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B56.