All-trans retinoic acid (ATRA) reduces proliferative capacity and Brachyury levels in the chordoma cell line UCH-1

Helena Robinson,Ramsay J Mcfarlane,Jane A Wakeman

doi:10.1017/exp.2020.31

Abstract

AbstractChordoma is a rare bone cancer for which there are no approved drugs. Surgery is the principle treatment but complete resection can be challenging due to the location of the tumours in the spine and therefore finding an effective drug treatment is a pressing unmet clinical need. A major recent study identified the transcription factor Brachyury as the primary vulnerability and drug target in chordoma. Previously, all-trans retinoic acid (ATRA) has been shown to negatively influence expression of the Brachyury gene, TBXT. Here we extend this finding and demonstrate that ATRA lowers Brachyury protein levels in chordoma cells and reduces proliferation of the chordoma cell line U-CH1 as well as causing loss of distinctive chordoma cell morphology. ATRA is available as a generic drug and is the first line treatment for acute promyelocytic leukaemia (APL). This study implies ATRA could have therapeutic value if repurposed for chordoma.

Highlights

Chordoma is a rare bone cancer with an annual incidence of 1 in 1,000,000 people and a poor prognosis
All-trans retinoic acid (ATRA) caused a reduction in Brachyury levels in both lines, this was less pronounced in JHC7 (Fig.1)
We treated U-CH1 cells with 20 μM ATRA and this resulted in the cell culture failing to increase cell numbers, validating the original study (Fig. 2)

Summary

Introduction

Chordoma is a rare bone cancer with an annual incidence of 1 in 1,000,000 people and a poor prognosis. It occurs mostly in the spine and whilst surgical resection is currently the most effective treatment this is difficult due to proximity to important structures. Chordomas are largely refractory to current chemotherapy, there is a pressing unmet clinical need for effective treatments (Stacchiotti & Sommer, 2015). U-CH1 chordoma cells treated with ATRA have reduced levels of TBXT (Brachyury gene) mRNA and reduced proliferative capacity (Aydemir et al, 2012). This study extends and validates these findings offering further insight into the mechanisms of ATRA as a potential chordoma therapeutic agent

Results

Discussion

Conclusion