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CDK4/6 dual inhibitor abemaciclib demonstrates compelling preclinical activity against esophageal adenocarcinoma: a novel therapeutic option for a deadly disease

2017; Impact Journals LLC; Volume: 8; Issue: 59 Linguagem: Inglês

10.18632/oncotarget.22244

1949-2553

Juliann E. Kosovec, Ali H. Zaidi, Ashten N. Omstead, Daisuke Matsui, Mark J. Biedka, Erin J. Cox, Patrick Campbell, Robert W Biederman, Ronan J. Kelly, Blair A. Jobe,

Metastasis and carcinoma case studies

// Juliann E. Kosovec 1 , Ali H. Zaidi 1 , Ashten N. Omstead 1 , Daisuke Matsui 2 , Mark J. Biedka 1 , Erin J. Cox 1 , Patrick T. Campbell 1 , Robert W.W. Biederman 3 , Ronan J. Kelly 4 and Blair A. Jobe 1 1 Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, PA, USA 2 Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan 3 McGinnis Cardiovascular Institute, Allegheny Health Network, Pittsburgh, PA, USA 4 Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, MD, USA Correspondence to: Ali H. Zaidi, email: Ali.zaidi@ahn.org Keywords: esophageal cancer; Cdk4 protein; CDK6 protein; abemaciclib; preclinical drug evaluations Received: September 15, 2017 Accepted: October 16, 2017 Published: November 01, 2017 ABSTRACT Esophageal adenocarcinoma (EAC) is a deadly disease with limited therapeutic options. In the present study, we determined the preclinical efficacy of CDK4/6 inhibitor abemaciclib for treatment of EAC. In vitro , apoptosis, proliferation, and pathway regulation were evaluated in OE19, OE33, and FLO1 EAC cell lines. In vivo , esophagojejunostomy was performed on rats to induce EAC. At 36 weeks post-surgery, MRI and endoscopic biopsy established baseline tumor volume and molecular correlates, respectively. Next, the study animals were randomized to 26mg/kg intraperitoneal abemaciclib treatment or vehicle control for 28 days. Pre and post treatment MRIs, histopathology, and qRT-PCR were utilized to determine response. Our results demonstrated treatment with abemaciclib lead to increased apoptosis, and decreased proliferation in OE19 (p=0.185), OE33 (p=0.048), and FLO1 (p=0.043) with anticipated downstream molecular inhibition. In vivo , 78.9% of treatment animals demonstrated >20% tumor volume decrease (placebo 0%). Mean tumor volume changed in the treatment arm by -65.5% (placebo +133.5%) (p<0.01), and prevalence changed by -37.5% (placebo +16.7%) (p<0.01). Pre vs post treatment qRT-PCR demonstrated significant inhibition of all downstream molecular correlates. Overall our findings suggest potent antitumor efficacy of abemaciclib against EAC with evident molecular pathway inhibition and reasonable safety, establishing the rationale for future clinical development.