On-target PIM-1 and STAT3 inhibition thwarts disease progression in xenografts of gastric cancer stem-likecells

5^th Asia-Pacific Summit on Cancer Therapy

July 20-22, 2015 Brisbane, Australia

Meei-Ling Sheu1, Wan-Yu Lin2 and Hang-Yi Chou1

Posters Accepted Abstracts: J Cancer Sci Ther

Abstract :

Background: Peritoneal dissemination is characterized by an aggressive clinical course, therapeutic resistance, and striking molecular heterogeneity. Cancer stem-likecells (CSCs) closely model this molecular heterogeneity and likely have a key role in tumor recurrence and therapeutic resistance. Emerging evidence indicates that signal transducer and activator of transcription3 (STAT3) is an important mediator of tumor cell survival, growth, and invasion in peritoneal dissemination that correlated with PIM-1 expression. Herein, we generated characterized 12 clones cells populations in gastric tumors with distinct properties that have stem cell-like characteristics, to evaluate the translational potential therapeutics by PIM-1 inhibitors. Methods: CSCs were cultured inDoxorubicin resistant condition;condense sphericity and highlyexpression of stem cells marker (CD133, CD44, DLL4 and LGR5) were determined by soft agar, real-time PCR. Endogenous PIM-1 and STAT3 activity was assessed in human gastric tissue, CSCs and animal xenografts by immunohistochemistry, PET/CT and Western blotting. PIM-1 inhibitors were used to inhibit PIM-1 and STAT3 activity in vitro and in vivo. Results: Both PIM-1 and STAT3 activity was demonstrated to be highly activated in human gastric tissue, molecularly heterogeneous CSCs tumors and CSCs xenografts. PIM-1 inhibitors or PIM-1 siRNA knockdown administration resulted in on-target STAT3 inhibition and dramatically reduced CSCs survival, soft agar assay and stem cells markers. CSCs animal xenografts maintained high levels of activated PIM-1 and STAT3 activity seen in their parent tumors. Intraperitoneal PIM-1 inhibitors reduced intratumoral PIM-1 and STAT3 activity,stem cells marker and prolonged animal survival. Conclusion: Our study demonstrates the in vitro and in vivo efficacy of on-target PIM-1 and STAT3 inhibition in heterogeneous CSCs that closely emulate the genomic and tumorigenic characteristics of molecular heterogeneityin cancer stem-likecells.