Abstract 1066: BMS-754807, a small-molecule inhibitor of insulin-like growth factor-1 receptor/insulin receptor is cytotoxic to esophageal adenocarcinoma cells and enhances nab-paclitaxel response in experimental esophageal adenocarcinoma
Authors: Hassan Md Sazzad , Cwidak Nicholas , Johnson Chloe , Ponna Saisantosh , Awasthi Niranjan , von Holzen Urs 
Published: June 2022

Introduction: Esophageal adenocarcinoma (EAC) is one of the fastest growing cancers in the Western world and the overall 5-year survival rate of EAC is below 20 percent. Epidemiological studies have linked obesity with EAC. Insulin-like growth factor (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 have 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. In this study, we evaluated the potential of targeting IGF signaling and improvement in nab-paclitaxel response by the addition of BMS-754807 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, cell apoptosis, cell migration and cell cycle analyses of EAC cell lines detected respectively by WST-1 assay, Western blotting, would healing scratch assay and propidium iodide flow cytometry. We then explored the antitumor efficacy of BMS-754807 and nab-paclitaxel monotherapy and in combination in murine subcutaneous xenograft and peritoneal metastatic survival models of human EAC.

Results: BMS-754807 dose-dependently inhibited in-vitro cell proliferation of EAC cell lines having phosphorylation of IGF-1R/IR protein. The co-administration of BMS-754807 and nab-paclitaxel effectively enhanced cell growth inhibition, cleavage of caspase-3 and PARP, in-vitro wound healing inhibition and cell cycle arrest at sub G0/G1 phase. BMS-754807 in combination with nab-paclitaxel treatment resulted in significantly higher antitumor efficacy by increasing intratumoral apoptosis and survival benefit compared with BMS-754807 or nab-paclitaxel treatment alone. 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). There was a significant increase in median animal survival after BMS-754807 plus nab-paclitaxel treatment (85 days) compared to control (47 days, p=0.0034), BMS-754807 monotherapy (57 days, p=0.0021) or nab-paclitaxel (68 days, p=0.0339) monotherapy.

Conclusion: 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, Nicholas Cwidak, Chloe Johnson, Saisantosh Ponna, Niranjan Awasthi, Urs von Holzen. BMS-754807, a small-molecule inhibitor of insulin-like growth factor-1 receptor/insulin receptor is cytotoxic to esophageal adenocarcinoma cells and enhances nab-paclitaxel response in experimental esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1066.