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

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

Research output: Contribution to journalArticle

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 postsurgery, 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.

Original languageEnglish (US)
Pages (from-to)100421-100432
Number of pages12
JournalOncotarget
Volume8
Issue number59
DOIs
StatePublished - Jan 1 2017

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Adenocarcinoma
Tumor Burden
Placebos
Therapeutics
Apoptosis
Polymerase Chain Reaction
5-(4-ethylpiperazin-1-ylmethyl)pyridin-2-yl)-(5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzimidazol-5-yl)pyrimidin-2-yl)amine
Biopsy
Safety
Cell Line

Keywords

  • Abemaciclib
  • Cdk4 protein
  • CDK6 protein
  • Esophageal cancer
  • Preclinical drug evaluations

ASJC Scopus subject areas

  • Oncology

Cite this

CDK4/6 dual inhibitor abemaciclib demonstrates compelling preclinical activity against esophageal adenocarcinoma : A novel therapeutic option for a deadly disease. / Kosovec, Juliann E.; Zaidi, Ali H.; Omstead, Ashten N.; Matsui, Daisuke; Biedka, Mark J.; Cox, Erin J.; Campbell, Patrick T.; Biederman, Robert W.W.; Kelly, Ronan Joseph; Jobe, Blair A.

In: Oncotarget, Vol. 8, No. 59, 01.01.2017, p. 100421-100432.

Research output: Contribution to journalArticle

Kosovec, JE, Zaidi, AH, Omstead, AN, Matsui, D, Biedka, MJ, Cox, EJ, Campbell, PT, Biederman, RWW, Kelly, RJ & Jobe, BA 2017, 'CDK4/6 dual inhibitor abemaciclib demonstrates compelling preclinical activity against esophageal adenocarcinoma: A novel therapeutic option for a deadly disease', Oncotarget, vol. 8, no. 59, pp. 100421-100432. https://doi.org/10.18632/oncotarget.22244
Kosovec, Juliann E. ; Zaidi, Ali H. ; Omstead, Ashten N. ; Matsui, Daisuke ; Biedka, Mark J. ; Cox, Erin J. ; Campbell, Patrick T. ; Biederman, Robert W.W. ; Kelly, Ronan Joseph ; Jobe, Blair A. / CDK4/6 dual inhibitor abemaciclib demonstrates compelling preclinical activity against esophageal adenocarcinoma : A novel therapeutic option for a deadly disease. In: Oncotarget. 2017 ; Vol. 8, No. 59. pp. 100421-100432.
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