Novel therapeutic strategy targeting the Hedgehog signalling and mTOR pathways in biliary tract cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Signaling Pathways

Background:

• Biliary tract cancer (BTC) frequently exhibits activation of the PI3K/mTOR and Hedgehog (Hh) signaling pathways.
• Crosstalk between these pathways is observed in other gastrointestinal cancers.
• The PI3K/mTOR inhibitor rapamycin and Hh inhibitor vismodegib may offer synergistic effects against BTC and cancer stem cells (CSCs).

Purpose of the Study:

• To investigate the synergistic effects of rapamycin and vismodegib on BTC cell lines, preclinical models, and CSCs.
• To evaluate the impact of combined PI3K/mTOR and Hh pathway inhibition on BTC growth and stemness markers.

Main Methods:

• Gene expression profiling of p70S6k and Gli1 in BTC cell lines.
• Assessment of tumor and pathway inhibitory effects of rapamycin and vismodegib in BTC preclinical models and CSCs.
• Western blotting to analyze key protein expression levels.

Main Results:

• Rapamycin and vismodegib synergistically reduced BTC cell viability and proliferation, arresting cells in G1 phase for Mz-ChA-1 cells.
• Combined treatment inhibited CSC and ALDH-positive cell proliferation, decreasing Nanog and Oct-4 expression.
• Significant inhibition of tumor growth (80%) and prolonged doubling time were observed in a xenograft model; key pathway proteins (p-p70S6K, p-Gli1, p-mTOR, p-AKT) were downregulated.

Conclusions:

• Targeted inhibition of the PI3K/mTOR and Hh pathways represents a novel therapeutic strategy for BTC.
• Combination therapy with PI3K/mTOR and Hh inhibitors demonstrates significant anti-tumor activity and CSC suppression in BTC.
• This approach warrants further clinical investigation for biliary tract cancer treatment.