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

  • NPJ Precis Oncol. 2025 Dec 10. doi: 10.1038/s41698-025-01219-7.
Kai Tian  #  1 ,  Yafei Jiang  #  1 ,  Mengxiong Sun  #  1 ,  Yu Lv  #  1 ,  Jean Fan  2 ,  Caixia Sun  3 ,  Yujia Zhu  3 ,  Yingying Yu  3 ,  Xiaoyan Qiang  3 ,  Peng Peng  3 ,  Frank Wu  3 ,  Weisong Zhao  1 ,  Dongqing Zuo  1 ,  Hongsheng Wang  1 ,  Chongren Wang  1 ,  Wei Sun  1 ,  Jinzeng Wang  4 ,  Zhengdong Cai  5 ,  Yingqi Hua  6
Affiliations
  • 1. Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China.
  • 2. TransThera Sciences (US), Inc, Gaithersburg, MA, USA.
  • 3. TransThera Sciences (Nanjing), Inc, Nanjing, China.
  • 4. National Research Center for Translational Medicine at Shanghai, State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 5. Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China. [email protected].
  • 6. Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41372533 DOI: 10.1038/s41698-025-01219-7
Abstract

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.

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