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Poster display session

5159 - Dual CDK 4/6 inhibitor demonstrates potent antitumor efficacy in vitro and in vivo against esophageal adenocarcinoma

Date

09 Sep 2017

Session

Poster display session

Presenters

Ashten Omstead

Citation

Annals of Oncology (2017) 28 (suppl_5): v209-v268. 10.1093/annonc/mdx369

Authors

A.N. Omstead1, J.E. Kosovec1, M.J. Biedka1, R.W.W. Biederman2, R.J. Kelly3, A.H. Zaidi1, B.A. Jobe1

Author affiliations

  • 1 Esophageal And Lung Institute, Allegheny Health Network, 15224 - Pittsburgh/US
  • 2 Mcginnis Cardiovascular Institute, Allegheny Health Network, 15224 - Pittsburgh/US
  • 3 Department Of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, 21231 - Baltimore/US
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Resources

Abstract 5159

Background

Esophageal adenocarcinoma (EAC) is a leading cause of cancer deaths, and current treatment options are limited. Cell cycle regulators CDK4 and CDK6 are progressively upregulated in EAC carcinogenesis and associated with poor prognosis. The modified Levrat model of esophagojejunostomy (EJ) in a rat has demonstrated well-documented utility for in vivo efficacy testing against de novo EAC. In the present study, we evaluate a dual CDK4/6 inhibitor, abemaciclib, for the treatment of EAC.

Methods

Human EAC cell lines, OE33 and FLO1, were used to evaluated proliferation and apoptosis using BrdU and flow cytometry, respectively. EJ was performed on 38 Sprague-Dawley rats to induce gastroduodenoesophageal reflux and the subsequent development of EAC. At 36 weeks post-operatively, rats were randomized to receive IP abemaciclib at 26 mg/kg per day or placebo (acetate buffer) for 4 weeks. Drug efficacy was evaluated with MRI, endoscopic biopsy, gross histological evaluation, and CDK4/6 pathway expression by RT-PCR.

Results

With an established ED50 of 6µM in OE33 and 14µM in FLO1, proliferation decreased with treatment by 89.5% and 87.5%, respectively. Flow cytometry demonstrated an increase of apoptosis by 45.6% and 38.9%, respectively. Twenty of 23 (87.0%) treated animals and all of 18 (100%) control animals reached study endpoint. Treatment group mortality consisted of rats afflicted with moderate peritonitis, diarrhea, and weight loss. Mean MRI tumor volume decreased by 151.0% in treatment animals and increased by 108.3% in control animals (p 

Conclusions

Abemaciclib exhibits potent in vitro and in vivo antitumor efficacy in EAC models, providing the rationale for future clinical testing.

Clinical trial identification

Legal entity responsible for the study

Eli Lilly and Co.

Funding

Eli Lilly and Co.

Disclosure

R.J. Kelly, A.H. Zaidi: Grant funding: Eli Lilly and Co. All other authors have declared no conflicts of interest.

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