2. Academic Validation
  3. KC1036, a multi-kinase inhibitor with anti-angiogenic activity, can effectively suppress the tumor growth of Ewing sarcoma

KC1036, a multi-kinase inhibitor with anti-angiogenic activity, can effectively suppress the tumor growth of Ewing sarcoma

  • Angiogenesis. 2025 Sep 18;28(4):50. doi: 10.1007/s10456-025-10008-6.
Xuejin Ou # 1,  Ge Gao # 2,  Qizhi Ma 1,  Diyuan Qin 2,  Kai Li 1,  Mingyang Feng 3,  Yu Gao 1,  Yao Zeng 1,  Yue Chen 2,  Xia He 2,  Ting Zhang 4,  Zeming Mo 5,  Benxia Zhang 2,  Inbar A Habaz 6,  Daxing Zhu 7,  Dan Li 8,  Yongsheng Wang 9 10
Affiliations

Affiliations

  • 1 Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 2 Clinical Trial Center, National Medical Products Administration Key Laboratory for Clinical Research and Evaluation of Innovative Drugs, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 3 Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 4 Laboratory of Neurological Disease Modeling and Translational Research, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 5 Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 6 Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
  • 7 Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 8 Institute of Respiratory Health, State Key Laboratory of Respiratory Health and Multimorbidity, Frontiers Science Center for Disease-Related Molecular Network, Sichuan Provincial Engineering Laboratory of Precision Medicine, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China. lidan@wchscu.cn.
  • 9 Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. wangys@scu.edu.cn.
  • 10 Clinical Trial Center, National Medical Products Administration Key Laboratory for Clinical Research and Evaluation of Innovative Drugs, West China Hospital, Sichuan University, Chengdu, Sichuan, China. wangys@scu.edu.cn.
  • # Contributed equally.
PMID: 40965696 DOI: 10.1007/s10456-025-10008-6
Abstract

Background: Ewing sarcoma (ES) is a rare but extremely aggressive bone and soft-tissue tumor. Clinical outcomes for patients with metastatic or recurrent ES remain poor, particularly for patients who are resistant to chemotherapy. This underscores an urgent need for alternative treatment strategies for these patients. A deep and comprehensive understanding of the cell-cell communications in ES may help identify new therapeutic approaches.

Methods: We first applied single-cell RNA Sequencing (scRNA-seq) data analysis to map the cell-cell communication network within the ES tumor microenvironment (TME). Then, based on the cell-cell communication map, we inferred that multi-kinase anti-angiogenic inhibitors might effectively treat ES. Therefore, we investigated the anti-tumor efficacy of a novel multi-kinase inhibitor, KC1036, which primarily targets VEGFR2, MET, and Axl in ES Cancer cell lines. The efficacy of KC1036 in ES was further validated in cell line-derived xenograft (CDX) models and a treatment-naïve patient-derived xenograft (PDX) model.

Results: We plotted a comprehensive cell-cell communication map of ES, where ES was characterized by highly immunosuppressive TME, strong autocrine signal NPY-NPY1R in tumor cells, wide activation of receptor kinase signaling pathways in cancer-associated fibroblasts (CAFs) (e.g., Axl, MET, FGFR, PDGFR, and KIT), and robust activation of tumor angiogenesis pathways (e.g., VEGFA/B-VEGFR1/2). Multi-kinase inhibitor KC1036 effectively inhibited ES tumor growth in both CDX and PDX models with superior efficacy compared to pazopanib, cabozantinib, and doxorubicin (DOX).

Conclusions: The novel anti-angiogenic inhibitor, KC1036, is effective in treating ES in the preclinical models.

Keywords

Anti-angiogenesis; Cell–cell communication; Ewing sarcoma.

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