Members Members Residents Job Board
Join Today Renew Your Membership Make A Donation
2007 Abstracts: Targeting MEK Is Effective Chemoprevention of hepatocellular carcinoma in TGF-α Transgenic Mice
Back to 2007 Program and Abstracts
Targeting MEK Is Effective Chemoprevention of hepatocellular carcinoma in TGF-α Transgenic Mice
Sabrina C. Wentz*1, Huangbing Wu1, Michele T. Yip-Schneider1,2, Matthew E. Hennig1, Patrick Klein1,3, Judith Sebolt-Leopold5, C. Max Schmidt1,4
1Surgery, Indiana University School of Medicine, Indianapolis, IN; 2Indiana University Cancer Center, Indianapolis, IN; 3Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN; 4Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, IN; 5Pfizer Pharmaceuticals, Indianapolis, IN

Introduction: Hepatocellular carcinoma (HCC) yields >600,000 mortalities/year worldwide. MEK-ERK signaling has been implicated in the molecular pathogenesis of HCC. Hypothesis: MEK inhibition prevents HCC formation in a developmental animal model.
Methods: Transgenic mice overexpressing human transforming growth factor-α (TGF-α) spontaneously develop HCC, which is accelerated with diethylnitrosamine (DEN) (5mg/kg intraperitoneal x1) at age 14 days. Forty-two DEN-exposed transgenic mice were initiated on Trial I (20wks) or Trial II (35wks) at age 10 weeks. Treatment arms (n≥5/arm) were vehicle (control) or novel MEK inhibitor PD325901 (1 and 10 mg/kg) daily via orogastric lavage. Liver tissue was examined grossly and histologically for evidence of HCC, adenoma, and foci of altered hepatocytes (FAH). Proliferation and apoptosis were evaluated with Ki-67 and ApopTag® immunostains.
Results: In Trial I, 10 HCC formed in control, compared to 0 in combined treatment arms (p<0.05). HCC incidence was 44% in control compared to 0% in combined treatment arms (p<0.05). In Trial II, 14 HCC formed in control compared to 0 and 1 in 1mg/kg and 10 mg/kg treatment arms, respectively (p<0.05). HCC incidence was 50% in control compared to 0% (1mg/kg) and 20% (10mg/kg) in treatment arms (p<0.05). Mean HCC volume in control was 4474μL compared to 46μL in the 10mg/kg treatment arm. Microscopically, HCC analysis mirrored previous gross findings. In Trial I, incidences of adenoma (12%) and FAH (12%) were greater than in combined treatment arms (0%). In Trial II, incidences of adenoma (80%) and FAH (80%) were greater than in either treatment arm (40% and 20% in 1mg/kg, 33% and 67% in 10mg/kg). Apoptosis in FAH was increased in treatment arms of both trials compared to control. Ki-67 staining remained unchanged.
Conclusions: MEK inhibition with PD325901 is effective in HCC chemoprevention in a developmental animal model. The mechanism may involve lowering the apoptotic threshold of precancerous hepatocytes. This preclinical data suggests that MEK targeting is a promising method for human HCC chemoprevention.


Back to 2007 Program and Abstracts


Society for Surgery of the Alimentary Tract

Facebook Twitter YouTube

Email SSAT Email SSAT
500 Cummings Center, Suite 4400, Beverly, MA 01915 500 Cummings Center
Suite 4400
Beverly, MA 01915
+1 978-927-8330 +1 978-927-8330
+1 978-524-0498 +1 978-524-0498
Links
About
Membership
Publications
Newsletters
Annual Meeting
Join SSAT
Job Board
Make a Pledge
Event Calendar
Awards