• Juliann E Kosovec, Ali H Zaidi, Lori A Kelly, Christina L Rotoloni, Christopher Vytlacil, Christina DiCarlo, Daisuke Matsui, Yoshihiro Komatsu, Natalie H Boyd, Ashten Omstead, Elena L Kolano, Robert W W Biederman, Gene Finley, Jan F Silverman, Rodney J Landreneau, and Blair A Jobe.
• *Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, PA†Department of Pathology and Laboratory Medicine, Allegheny Health Network, Pittsburgh, PA‡McGinnis Cardiovascular Institute, Allegheny Health Network, Pittsburgh, PA§Division of Hematology and Oncology, Allegheny Health Network, Pittsburgh, PA.
• Ann. Surg. 2016 Aug 1; 264 (2): 297-304.

ObjectiveTo assess the efficacy of heat-shock protein 90 (Hsp90) inhibitor, NVP-AUY922-AG (AUY922), in the treatment of esophageal adenocarcinoma (EAC) in vitro and in vivo.BackgroundEAC is a leading cause of cancer death, and current treatment options are limited. Hsp90, a chaperone protein that regulates several oncoproteins, is upregulated in EAC, and may be a novel target for therapy.MethodsIn vitro, EAC cell lines were utilized to evaluate AUY922, alone and in combination with 5-fluorouracil (5-FU) and cisplatin. BrdU ELISA and flow cytometry were used to assess proliferation and measure apoptosis, respectively. Western blot and RT-PCR were performed to quantitate Hsp90 pathway expression. In vivo, esophagojejunostomy was performed on rats and treatment animals received AUY922 32 to 40 weeks postoperatively. Drug efficacy was evaluated with magnetic resonance imaging (MRI), endoscopic biopsy, gross histological evaluation, and Hsp90 pathway expression.ResultsIn vitro, AUY922 demonstrated antiproliferative activity in both cell lines and showed enhanced efficacy with cisplatin and 5-FU. Western Blot and RT-PCR demonstrated downregulation of CDK1 and CDK4 and upregulation of Hsp72. In vivo, AUY922 showed decrease in tumor volume in 36.4% of rats (control = 9.4%), increase in 9.1% (control = 37.5%), and stable disease in 54.5% (control = 43.7%). Necropsy confirmed the presence of EAC in 50% of treatment animals and 75% of control animals. mRNA expression, pre- and posttreatment, demonstrated significant downregulation of MIF, Hsp70, Hsp90β, and CDK4, and upregulation of Hsp72.ConclusionsAUY922 exhibits antitumor efficacy in vitro and in vivo for EAC, suggesting the need for human clinical trials.

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