Abstract B225: Use of RNAi to identify targets for further improving the antitumor activity of gemcitabine and nab-paclitaxel combination therapy in patients with advanced pancreatic cancer

Abstract

Abstract Pancreatic cancer remains the fourth leading cause of cancer-related deaths in the United States. Gemcitabine has been used as a standard first-line therapy for more than a decade for this deadly disease. However, the benefit of single-agent gemcitabine in advanced pancreatic cancer is small. Combination regimens including gemcitabine have provided only modest improvement. In a Phase I/II clinical trial gemcitabine plus nab-paclitaxel had significant clinical activity (Von Hoff, et al. 2009, J. Clin. Oncol. 27 (15s): Abstract #4525). To further improve the response of gemcitabine plus nab-paclitaxel therapy, we performed a high throughput RNAi (HT-RNAi) screen with a kinase-focused siRNA library consisting of siRNA oligos against 588 genes (2 siRNAs/gene) in the MIA PaCa-2 pancreatic cancer cell line. Eighty eight siRNAs targeting 82 genes were identified as positive hits (≥2 fold decrease in IC50 values). Several commercially available small molecule inhibitors of the positive hits were obtained and tested in combination with gemcitabine and nab-paclitaxel, both alone or in combination. Among the small molecule inhibitors tested, the CHK1 inhibitor, SB 218078, showed the most significant synergistic effect with gemcitabine and nab-paclitaxel, gemcitabine alone, or nab-paclitaxel alone in two pancreatic cancer cell lines, MIA PaCa-2 and PANC-1. The mechanism of SB 218078 induced sensitivity of pancreatic cancer cells to the gemcitabine and nab-paclitaxel are currently under investigation. In summary, using an HT-RNAi screen we have identified a list of gene targets that, when down-regulated by siRNA oligos, sensitize pancreatic cancer cells to the gemcitabine plus nab-paclitaxel combination therapy. Inhibitors of these targets may potentially enhance the anticancer activity of gemcitabine and nab-paclitaxel. (This work was supported by NIH/NCI Program Project grant CA109552). Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B225.