title: Augmentation of response to nab-paclitaxel by inhibition of insulin-like growth factor (IGF) signaling in preclinical pancreatic cancer models.
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.
authors.affiliation: Department of Surgery, Indiana University School of Medicine, South Bend, IN, USA.|Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, USA.
authors.forename: Niranjan
authors.initials: N
authors.lastname: Awasthi
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Scire
authors.affiliation: Department of Surgery, Indiana University School of Medicine, South Bend, IN, USA.
authors.forename: Sheena
authors.initials: S
authors.lastname: Monahan
authors.affiliation: Department of Psychology, University of Notre Dame, Notre Dame, IN, USA.
authors.forename: Meghan
authors.initials: M
authors.lastname: Grojean
authors.affiliation: Department of Surgery, Indiana University School of Medicine, South Bend, IN, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, South Bend, IN, USA.|Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Schwarz
authors.affiliation: Department of Surgery, Indiana University School of Medicine, South Bend, IN, USA.|Indiana University Health Goshen Center for Cancer Care, Goshen, IN, USA.
authors.forename: Roderich E
authors.initials: RE
authors.lastname: Schwarz
mesh_terms: D000418:Albumins / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020128:Inhibitory Concentration 50; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000556:secondary; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D013002:Somatomedins / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; C545990:BMS 754807; C000597236:IGF1R protein, human; D011720:Pyrazoles; D017451:Receptors, Somatomedin; D013002:Somatomedins; D014227:Triazines; D017526:Receptor, IGF Type 1; C505407:CASP3 protein, human; D053148:Caspase 3; D017239:Paclitaxel
keywords: BMS-754807; IGF-1R; combination therapy; nab-paclitaxel; pancreatic cancer