Oncotarget

Research Papers:

Augmentation of response to nab-paclitaxel by inhibition of insulin-like growth factor (IGF) signaling in preclinical pancreatic cancer models

Niranjan Awasthi _, Emily Scire, Sheena Monahan, Meghan Grojean, Eric Zhang, Margaret A. Schwarz and Roderich E. Schwarz

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Oncotarget. 2016; 7:46988-47001. https://doi.org/10.18632/oncotarget.9029

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Abstract

Niranjan Awasthi1,5, Emily Scire2, Sheena Monahan1, Meghan Grojean3, Eric Zhang1, Margaret A. Schwarz4,5 and Roderich E. Schwarz1,6

1 Department of Surgery, Indiana University School of Medicine, South Bend, IN, USA

2 Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA

3 Department of Psychology, University of Notre Dame, Notre Dame, IN, USA

4 Department of Pediatrics, Indiana University School of Medicine, South Bend, IN, USA

5 Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, USA

6 Indiana University Health Goshen Center for Cancer Care, Goshen, IN, USA

Correspondence to:

Niranjan Awasthi, email:

Keywords: pancreatic cancer, nab-paclitaxel, IGF-1R, BMS-754807, combination therapy

Received: December 16, 2015 Accepted: April 16, 2016 Published: April 26, 2016

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.


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