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Society for Surgery of the Alimentary Tract

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Teena Dhir*1, Christopher Schultz1, Aditi Jain1, Charles J. Yeo1, Talia Golan2, Jonathan R. Brody1
1Surgery, Thomas Jefferson University, Philadelphia, PA; 2Oncology, Chaim Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv, Israel

Objective: Pancreatic Ductal Adenocarcinoma (PDA) is a devastating malignancy with a 9% five-year survival rate and is the third leading cause of cancer-related deaths in the U.S One common genetic feature in PDA is the loss of the CDKN2A gene expression (p16) which is found in over 90% of tumor samples. P16 inhibits the activity of the cyclin D-CDK4/6 complex leading to a G1 arrest, thus p16 loss leads to unchecked cellular proliferation. We hypothesized that the established FDA approved, CDK4/6 inhibitor, abemaciclib (Lilly, IN), could be a potent targeted strategy by inhibiting this commonly dysregulated pathway in PDA cells.
Methods: We determined the efficacy of abemaciclib, an oral CDK4/6 inhibitor in vitro and in vivo in PDA cell lines. IC50 were calculated in multiple PDA cell lines with known P16 status, along with characterizing abemaciclib's effect on cell cycle progression, apoptosis and senescence. In vivo, athymic female nude mice were engrafted with human PDA, Mia PaCa2 cells and randomized to treatment and control arms.
Results: In vitro, we tested CDK4/6 inhibitors palbociclib and abemaciclib in multiple pancreatic cell lines and found that abemaciclib was more potent with IC50s as low as 100nM and caused significant G1 arrest. Abemaciclib was able to not only induce senescence, but also induce apoptosis in PDA cell lines contributing to its efficacy. In vivo, daily abemaciclib therapy was safe and lead to a statistically significant decrease in tumor volume compared to no treatment (p<0.0001) and gemcitabine (p=0.0002).
Conclusion: Abemaciclib had comparable potency to current chemotherapeutics, inhibited colony formation, lead to G1/S arrest and induced apoptosis and senescence. In vivo, abemaciclib lead to tumor growth inhibition in our pilot study. Future work aims to find synergistic drug combination therapy in PDA in an effort to move this work towards a PDA-specific clinical trial.

Athymic nude mice were implanted with Mia PaCa2 xenografts on bilateral flanks and were randomized to no treatment arm, abemaciclib, 75 mg/kg PO, daily (n=5) or gemcitabine, 50mg/kg IP, weekly (n=5). Tumor volume measurements, along with tumor volume fold change, were calculated and plotted over time. Mouse weights were also recorded and plotted over time.

IHC analysis of paraffin embedded xenograft tumors and probed for phospho-Rb, ser 807/811, total Rb, Ki67 looking at proliferative index and TUNEL looking at DNA fragmentation. On TUNEL staining, black arrows pointing towards positively stained nuclei.

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