Systematic review of novel target therapies and clinical trials in chordoma.

INTRODUCTION: Chordoma represents a central nervous system tumor with an incidence of 8.4 per 10 million individuals in the U.S. Current treatment options include surgical resection and radiotherapy. Despite recent studies demonstrating significant improvement in molecular understanding of disease, treatment options remain limited.

OBJECTIVES: To evaluate a database of high-throughput drug screening in conjunction with a systematic literature review of potential novel target sites.

METHODS: A systematic review using terms "chordoma" AND "targeted therapy" OR "clinical trial" yielded 4560 articles, which were screened, and a total of 88 were included in the final analysis. Evaluation of the Chordoma Foundation high-throughput drug screening database was cross-referenced with published literature.

RESULTS: Targeted therapies mostly involved receptor tyrosine kinase inhibitors. Cyclin-dependent kinase (CDK) inhibitors suppressed chordoma cell proliferation and brachyury expression in vitro and xenograft models. Epigenetic modulators showed therapeutic promise by altering chromatin states associated with brachyury overexpression. Genomic analyses showed recurrent alterations in TBXT, CDKN2A/B, PTEN, and chromatin remodeling genes such as SMARCB1 and PBRM1. Immunotherapeutic approaches had efficacy in preclinical models through PD-L1 blockade, NK, and CAR-T cell strategies. Vaccine-based therapies showed limited clinical benefit. RNA-based therapies represent emerging strategies that need more studies.

CONCLUSION: Biomarker-guided repurposing of therapies approved in other tumors remains the fastest path to redefining the treatment model, but chordoma rarity and low mutation burden limit the impact of genomics in target discovery. This analysis indicates several potential candidate drugs that may be rapidly deployable in a clinical trial setting.