• Ali H Zaidi, Juliann E Kosovec, Daisuke Matsui, Ashten N Omstead, Moses Raj, Rohit R Rao, BiedermanRobert W WRWW, Gene G Finley, Rodney J Landreneau, Ronan J Kelly, and Blair A Jobe.
• *Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, PA †Division of Hematology and Oncology, Allegheny Health Network, Pittsburgh, PA ‡McGinnis Cardiovascular Institute, Allegheny Health Network, Pittsburgh, PA §Landreneau Thoracic Surgical Associates, Kittanning, PA ¶Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD.
• Ann. Surg. 2017 Jul 1; 266 (1): 91-98.

ObjectiveThe purpose of the current study is to determine the efficacy of a PI3K/mTOR dual inhibitor, LY3023414, on established EAC in an in vivo model.BackgroundEsophageal adenocarcinoma (EAC) is a highly lethal cancer with limited treatment options. The PI3K/mTOR pathway is upregulated in EAC and may be a target for novel therapies.MethodsEsophagojejunostomy was performed on Sprague-Dawley rats to induce carcinogenesis, and LY3023414 was cyclically administered intraperitoneally between 32 and 40 weeks postsurgery to treatment animals. Magnetic resonance imaging (MRI) and histology were used to determine clinical response. Immunohistochemistry, immunofluorescence, and Western blot were used to validate apoptosis by cleaved caspase-3, proliferation by Ki67, and pathway inhibition, respectively.ResultsMean MRI tumor volume increased by 109.2% in controls (n = 32) and decreased by 56.8% in treatment animals (n=17) (P < 0.01). Treatment with LY3023414 demonstrated tumor volume increase in 0% (control = 46.4%) (P < 0.01), decrease in 58.8% (control = 7.1%) (P < 0.01), and stable volume in 41.2% (control = 46.4%) (P = 0.77). EAC prevalence in controls increased by 25%; whereas, prevalence in treatment animals decreased by 29.4% (P < 0.01). Approximately, 75% of treatment animals presenting with residual masses on MRI had a histological response >50%. Increased apoptosis by cleaved caspase-3 (P = 0.03) and decreased proliferation by Ki67 (P < 0.01) were demonstrated in the treatment arm, when compared with the control arm. On Western blot analysis of pathway checkpoints, p-mTOR (p=0.03) and PI3K-α (P = 0.04) were downregulated in treatment responsive residual tumors, when compared with controls.ConclusionsLY3023414 demonstrates efficacy against EAC in a preclinical model, establishing the rationale for clinical testing.

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