Abstract
Nab-paclitaxel has recently shown greater efficacy in pancreatic ductal adenocarcinoma (PDAC). Insulin like growth factor (IGF) signaling proteins are frequently overexpressed in PDAC and correlate with aggressive tumor phenotype and poor prognosis. We evaluated the improvement in nab-paclitaxel response by addition of BMS-754807, a small molecule inhibitor of IGF-1R/IR signaling, in preclinical PDAC models. In subcutaneous xenografts using AsPC-1 cells, average net tumor growth in different therapy groups was 248.3 mm3 in controls, 42.4 mm3 after nab-paclitaxel (p = 0.002), 93.3 mm3 after BMS-754807 (p = 0.01) and 1.9 mm3 after nab-paclitaxel plus BMS-754807 (p = 0.0002). In subcutaneous xenografts using Panc-1 cells, average net tumor growth in different therapy groups was: 294.3 mm3 in controls, 23.1 mm3 after nab-paclitaxel (p = 0.002), 118.2 mm3 after BMS-754807 (p = 0.02) and −87.4 mm3 (tumor regression) after nab-paclitaxel plus BMS-754807 (p = 0.0001). In peritoneal dissemination model using AsPC-1 cells, median animal survival was increased compared to controls (21 days) after therapy with nab-paclitaxel (40 days, a 90% increase, p = 0.002), BMS-754807 (27 days, a 29% increase, p = 0.01) and nab-paclitaxel plus BMS-754807 (47 days, a 124% increase, p = 0.005), respectively. Decrease in proliferation and increase in apoptosis by nab-paclitaxel and BMS-754807 therapy correlated with their in vivo antitumor activity. In vitro analysis revealed that the addition of IC25 dose of BMS-754807 decreased the nab-paclitaxel IC50 of PDAC cell lines. BMS-754807 therapy decreased phospho-IGF-1R/IR and phospho-AKT expression, and increased cleavage of caspase-3 and PARP-1. These results support the potential of BMS-754807 in combination with nab-paclitaxel as an effective targeting option for pancreatic cancer therapy.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer-related deaths in developed countries [1]
IGF1R shares significant structural homology with insulin receptor (IR), and targeting Insulin like growth factor (IGF) pathway with IGF-1 receptor (IGF-1R) inhibitor antibodies is sensible as it only blocks IGF-1R induced mitogenic signaling but is not affecting IR signaling, which could lead to dysregulation of glucose homeostasis [20, 21]
Since IGF-1R and IR are highly homologous, antagonist development was initially focused towards monoclonal antibodies that selectively target IGF-1R and not affect IR signaling, which could lead to dysregulation of glucose homeostasis [21]
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer-related deaths in developed countries [1]. Less than 20% of PDAC patients are amenable to a curative surgical resection due to late clinical presentation, and early and aggressive local and metastatic progression [4] Even among these patients, postoperative recurrence remains commonplace [5, 6], leading to a 5-year survival at less than 20% [7]. Nab-paclitaxel (NPT), a water-soluble albumin-bound paclitaxel, has recently shown efficacy against advanced PDAC [10, 11], and nab-paclitaxel in combination with gemcitabine demonstrated 8.5 months median survival compared with 6.7 months after gemcitabine alone [12]. Considering these trial-based moderate improvements in PDAC prognosis, there is an urgent requirement for novel therapeutic strategies to improve overall patient survival
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