title: PI3K/mTOR Dual Inhibitor, LY3023414, Demonstrates Potent Antitumor Efficacy Against Esophageal Adenocarcinoma in a Rat Model.
abstract: The 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.
  
  
  
  Esophageal 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.
  
  
  
  Esophagojejunostomy 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.
  
  
  
  Mean 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.
  
  
  
  LY3023414 demonstrates efficacy against EAC in a preclinical model, establishing the rationale for clinical testing.
authors.affiliation: *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.
authors.forename: Ali H
authors.initials: AH
authors.lastname: Zaidi
authors.forename: Juliann E
authors.initials: JE
authors.lastname: Kosovec
authors.forename: Daisuke
authors.initials: D
authors.lastname: Matsui
authors.forename: Ashten N
authors.initials: AN
authors.lastname: Omstead
authors.forename: Moses
authors.initials: M
authors.lastname: Raj
authors.forename: Rohit R
authors.initials: RR
authors.lastname: Rao
authors.forename: Robert W W
authors.initials: RWW
authors.lastname: Biederman
authors.forename: Gene G
authors.initials: GG
authors.lastname: Finley
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Landreneau
authors.forename: Ronan J
authors.initials: RJ
authors.lastname: Kelly
authors.forename: Blair A
authors.initials: BA
authors.lastname: Jobe
mesh_terms: D000230:Adenocarcinoma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D004938:Esophageal Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D011725:Pyridines / Q000627:therapeutic use*; D015363:Quinolones / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D047368:Tumor Burden
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; C000621566:LY3023414; C574981:PI3KAP protein, rat; D011725:Pyridines; D015363:Quinolones; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases