CTOS 2024: Promoting replication stress is an actionable therapeutic opportunity in chordoma

Last year, our research team identified that pre-clinical chordoma models were exceptionally sensitive to drugs that target replication stress. Replication stress occurs when DNA in a cell is being copied, or replicated, and encounters a “stress” that can compromise this process. This phenomenon appears to be elevated in chordoma. The therapeutic concept is to have a drug that exacerbates replication stress, such as gemcitabine, which is a widely-used, low-cost cancer drug, and the other is to remove the ability of the cancer cell to remedy replication stress, which can be achieved by using a class of drugs called ATR inhibitors. When combined, these drugs are exceptionally synergistic. This is because gemcitabine exacerbates replication stress and ATR inhibitors remove the ability for the chordoma cell to fix it. This drug combination serves as a proof-of-concept that drugs targeting this phenomenon can be a viable option for the treatment of chordoma. Gemcitabine and ATR inhibitors are not the only two drugs that target replication stress, so the team is also exploring other combinations of drugs within these pathways to get this therapeutic concept into the clinic as a treatment for patients as quickly as possible. More about these potential new therapeutic options can be found here.