BACKGROUND: Standard therapy for chordoma consists of surgical resection 
followed by high-dose irradiation. Protein phosphatase 2A (PP2A) is a 
ubiquitously expressed serine/threonine phosphatase involved in signal 
transduction, cell cycle progression, cell differentiation, and DNA repair. 
LB100 is a small-molecule inhibitor of PP2A designed to sensitize cancer cells 
to DNA damage from irradiation and chemotherapy. A recently completed phase I 
trial of LB100 in solid tumors demonstrated its safety. Here, we show the 
therapeutic potential of LB100 in chordoma.
METHODS: Three patient-derived chordoma cell lines were used: U-CH1, JHC7, and 
UM-Chor1. Cell proliferation was determined with LB100 alone and in combination 
with irradiation. Cell cycle progression was assessed by flow cytometry. 
Quantitative γ-H2AX immunofluorescence and immunoblot evaluated the effect of 
LB100 on radiation-induced DNA damage. Ultrastructural evidence for nuclear 
damage was investigated using Raman imaging and transmission electron 
microscopy. A xenograft model was established to determine potential clinical 
utility of adding LB100 to irradiation.
RESULTS: PP2A inhibition in concert with irradiation demonstrated in vitro 
growth inhibition. The combination of LB100 and radiation also induced 
accumulation at the G2/M phase of the cell cycle, the stage most sensitive to 
radiation-induced damage. LB100 enhanced radiation-induced DNA double-strand 
breaks. Animals implanted with chordoma cells and treated with the combination 
of LB100 and radiation demonstrated tumor growth delay.
CONCLUSIONS: Combining LB100 and radiation enhanced DNA damage-induced cell 
death and delayed tumor growth in an animal model of chordoma. PP2A inhibition 
by LB100 treatment may improve the effectiveness of radiation therapy for 
chordoma.