Abstract 4813: Enhancement of nab-paclitaxel response by inhibition of insulin-like growth factor (IGF) signaling in experimental esophageal adenocarcinoma

Introduction: Esophageal adenocarcinoma (EAC) is the fastest growing cancer in the western world and the overall 5 year survival rate of EAC is below 20 percent. Most patients with EAC present with locally advanced or widespread metastatic disease, where current treatment is largely ineffective. Therefore, new therapeutic approaches are urgently needed. Epidemiological studies have linked obesity with EAC. IGF signaling is an important mediator in obesity-associated EAC. Paclitaxel (PT) has been used in combination with carboplatin as a standard combination therapy for advanced EAC. PT required emulsification with solvents which has resulted in serious adverse effects in patients. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is an albumin-stabilized, cremophor-free and water soluble nanoparticle formulation of PT. Nab-paclitaxel has recently shown greater efficacy over PT in EAC. Here we evaluated the improvement in nab-paclitaxel response by addition of BMS-754807, a small molecule inhibitor of IGF-1R/IR signaling, in experimental EAC. Methods: We first evaluated the phosphorylation status of IGF-1R/IR protein by western blot in a panel of EAC cell lines. BMS-754807 and nab-paclitaxel, alone or in combination were tested for effects on cell growth detected by WST-1 assay and on cell apoptosis detected by western blot of cleavage of caspase 3 and PARP. We then explored the antitumor efficacy with survival advantage following BMS-754807 and nab-paclitaxel mono and combination therapies in murine subcutaneous xenograft and peritoneal metastatic survival models of human EAC. Results: BMS-754807 dose dependently inhibited in-vitro cell proliferation of OE19 and FLO-1 EAC cell lines having strong tyrosine phosphorylation of IGF-1R/IR protein and interestingly the addition of IC25 dose of BMS-754807 significantly decreased the nab-paclitaxel IC50 in these EAC cells. In addition, co-administration of BMS-754807 and nab-paclitaxel effectively enhanced cleavage of caspase-3 and PARP in these EAC cells. In subcutaneous xenografts using OE19 cells, average net tumor growth after two weeks in different therapy groups was 558.67 mm3 in control, 208.47 mm3 after BMS-754807 (p=0.043), 104.60 mm3 after nab-paclitaxel (p=0.013), and 14.30 mm3 after BMS-754807 plus nab-paclitaxel (p=0.0005). In OE19 EAC survival model there was a significant increase in median animal survival after two weeks BMS-754807 plus nab-paclitaxel treatment (85 days) compared to control (47 days, p=0.0034), to BMS-754807 therapy (57 days, p=0.0021) or to nab-paclitaxel (68 days, p=0.0339) therapy. Conclusion: Thus BMS-754807 with nab-paclitaxel treatment resulted in significantly higher antitumor efficacy and survival benefit. These results support the potential of BMS-754807 in combination with nab-paclitaxel as an effective option for EAC therapy. Citation Format: Md Sazzad Hassan, Fiona Williams, Niranjan Awasthi, Margaret A. Schwarz, Roderich E. Schwarz, Urs von Holzen. Enhancement of nab-paclitaxel response by inhibition of insulin-like growth factor (IGF) signaling in experimental esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4813.