TY - JOUR
T1 - CDK4/6 dual inhibitor abemaciclib demonstrates compelling preclinical activity against esophageal adenocarcinoma
T2 - A novel therapeutic option for a deadly disease
AU - Kosovec, Juliann E.
AU - Zaidi, Ali H.
AU - Omstead, Ashten N.
AU - Matsui, Daisuke
AU - Biedka, Mark J.
AU - Cox, Erin J.
AU - Campbell, Patrick T.
AU - Biederman, Robert W.W.
AU - Kelly, Ronan J.
AU - Jobe, Blair A.
N1 - Funding Information:
Grant support from Eli Lilly & Company.
Publisher Copyright:
© Kosovec et al.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Abemaciclib
KW - CDK6 protein
KW - Cdk4 protein
KW - Esophageal cancer
KW - Preclinical drug evaluations
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UR - http://www.scopus.com/inward/citedby.url?scp=85034655487&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.22244
DO - 10.18632/oncotarget.22244
M3 - Article
C2 - 29245989
AN - SCOPUS:85034655487
SN - 1949-2553
VL - 8
SP - 100421
EP - 100432
JO - Oncotarget
JF - Oncotarget
IS - 59
ER -