Targeting high-risk MYC-overexpressed osteosarcoma with an Aurora kinase inhibitor:--results from a pilot umbrella trial.

Osteosarcoma is a highly heterogeneous cancer, and molecular subtyping has the potential to increase diagnostic precision and facilitate targeted therapies. In our previous study, we classified osteosarcoma into four distinct subtypes. Here, we conducted a genomic subtype-guided pilot umbrella trial (ChiCTR2000036618, 2020/08/24) to evaluate the efficacy and safety of multiple precision therapies. Nineteen patients with refractory metastatic osteosarcoma were enrolled and stratified using whole-exome sequencing (WES) and immunohistochemistry (IHC). Patients were assigned to three arms: (A) PD-1 antibody plus gemcitabine and docetaxel; (B) PARP inhibitor combined with temozolomide; or (C) tinengotinib (TT-00420), a small-molecule aurora kinase inhibitor currently in clinical trials. The median progression-free survival and overall survival were 50 days (95% CI: 33-89) and 149 days (95% CI: 90-185). Tinengotinib has shown promising efficacy in our preclinical studies, suggesting its potential for clinical use, particularly in combination with immunotherapy. Additionally, we found that patients with MYC amplification presented increased tumor purity and ploidy, homologous recombination deficiency scores, and an immunosuppressive microenvironment. This study demonstrated the feasibility of using genomic molecular subtyping to guide the precise treatment of osteosarcoma. We also revealed that the abnormal genomic and transcriptomic profiles caused by MYC amplification could be suppressed by tinengotinib.