Ou Xuejin, Gao Ge, Ma Qizhi, Qin Diyuan, Li Kai, Feng Mingyang, Gao Yu, Zeng Yao, Chen Yue, He Xia, Zhang Ting, Mo Zeming, Zhang Benxia, Habaz Inbar A, Zhu Daxing, Li Dan, Wang Yongsheng
Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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.
Angiogenesis. 2025 Sep 18;28(4):50. doi: 10.1007/s10456-025-10008-6.
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.
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.
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).
The novel anti-angiogenic inhibitor, KC1036, is effective in treating ES in the preclinical models.
尤因肉瘤（ES）是一种罕见但极具侵袭性的骨和软组织肿瘤。转移性或复发性ES患者的临床结局仍然很差，尤其是对化疗耐药的患者。这凸显了为这些患者寻找替代治疗策略的迫切需求。深入全面地了解ES中的细胞间通讯可能有助于确定新的治疗方法。
我们首先应用单细胞RNA测序（scRNA-seq）数据分析来绘制ES肿瘤微环境（TME）内的细胞间通讯网络。然后，基于细胞间通讯图谱，我们推断多激酶抗血管生成抑制剂可能有效治疗ES。因此，我们研究了一种新型多激酶抑制剂KC1036在ES癌细胞系中的抗肿瘤疗效，该抑制剂主要靶向VEGFR2、MET和AXL。KC1036在ES中的疗效在细胞系衍生异种移植（CDX）模型和未经治疗的患者衍生异种移植（PDX）模型中得到进一步验证。
我们绘制了一张全面的ES细胞间通讯图谱，其中ES的特征是高度免疫抑制的TME、肿瘤细胞中强烈的自分泌信号NPY-NPY1R、癌症相关成纤维细胞（CAF）中受体激酶信号通路的广泛激活（例如AXL、MET、FGFR、PDGFR和KIT）以及肿瘤血管生成途径的强烈激活（例如VEGFA/B-VEGFR1/2）。多激酶抑制剂KC1036在CDX和PDX模型中均有效抑制ES肿瘤生长，与帕唑帕尼、卡博替尼和阿霉素（DOX）相比疗效更佳。
新型抗血管生成抑制剂KC1036在临床前模型中对治疗ES有效。
