Abstract
Gemcitabine has limited clinical benefits in pancreatic ductal adenocarcinoma (PDAC). Insulin-like growth factor (IGF) signaling proteins are frequently overexpressed in PDAC. The therapeutic potential of BMS-754807, a small-molecule inhibitor of IGF-type 1 receptor (IGF-1R) and insulin receptor (IR), and gemcitabine was evaluated in experimental PDAC. Cell proliferation and protein expression were measured by WST-1 assay and immunoblotting. Tumor growth and survival studies were conducted in murine xenografts. PDAC cells expressed phospho-IGF-1R protein. BMS-754807 and gemcitabine inhibited cell proliferation of PDAC cells; the combination of BMS-754807 with gemcitabine had additive effects. Addition of BMS-754807 decreased gemcitabine IC₅₀ from 9.7 μmol/L to 75 nmol/L for AsPC-1, from 3 μmol/L to 70 nmol/L for Panc-1, from 72 to 16 nmol/L for MIA PaCa-2, and from 28 to 16 nmol/L for BxPC-3 cells. BMS-754807 caused a decrease in phospho-IGF-1R and phospho-AKT proteins in AsPC-1 and Panc-1 cells. BMS-754807 and gemcitabine caused an increase in PARP-1 and caspase-3 cleavage. Net tumor growth inhibition in BMS-754807, gemcitabine, and BMS-754807+gemcitabine groups was 59%, 35%, and 94% as compared with controls. Effects of therapy on intratumoral proliferation and apoptosis corresponded with tumor growth inhibition data. BMS-754807 also caused a decrease in phospho-IGF-1R and phospho-AKT in tumor tissue lysates. Median animal survival (controls: 21 days) with BMS-754807 was 27 days (P = 0.03), with gemcitabine 28 days (P = 0.05), and in the BMS-754807+gemcitabine combination group, 41 days (P = 0.007). The strong antitumor activity of BMS-754807 in experimental PDAC supports the potential of BMS-754807-induced mechanisms for clinical PDAC therapy.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human cancers with extremely poor prognosis and 5-year survival is less than 5% [1]
Inhibition in cell proliferation of PDAC cells by BMS-754807 seems to correlate to their expression of phospho-Insulin-like growth factor (IGF)-1R (Fig. 1)
Local recurrence rate is very high in completely resected PDAC patients and they eventually require palliative treatment
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human cancers with extremely poor prognosis and 5-year survival is less than 5% [1]. More than 40,000 individuals are diagnosed with PDAC and this incidence nearly equals mortality mostly due to late clinical presentation, early and aggressive local and metastatic progression, and high resistance to conventional therapies. Gemcitabine (Gem), a nucleoside analog that exerts its cytotoxic effects mainly by being. The efficacy of gemcitabine as a single agent remains modest, with a median progression-free survival of approximately 6 months in randomized clinical trials and a 12-month survival of less than 20% [2,3,4].
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