Long Zuoyao, Lu Yajie, Li Minghui, Li Jing, Chen Guojing, Wang Fengwei, Wang Qi, Xiang Liangbi, Wang Zhen
General Hospital of Northern Theater Command, Shenyang, China.
Xijing Hospital, The Air Force Military Medical University, Xi'an, China.
Cancer Med. 2024 Dec;13(23):e70416. doi: 10.1002/cam4.70416.
The aim of this study was to analyze the potential therapeutic targets of anlotinib using the patient-derived xenografts (PDX) and evaluate the efficacy of the combination of chemotherapy and anlotinib in osteosarcoma patients before surgery.
Forty-three osteosarcoma specimens were used to establish the PDX model in mice, resulting in Twenty-one PDX successful models. Eventually, six models were randomly selected for the pharmacodynamic experiment. The tumor-bearing mice were randomly divided into the anlotinib (3 mg/kg) and placebo groups (n = 5 each). After treatment, the tumors were harvested and analyzed by immunohistochemistry (IHC) and western blotting.
In PDX model establishment, the tumors from donors with relapse, metastasis or chemoresistance demonstrated higher engraftment capacity. Histology results suggested that anlotinib significantly inhibited the growth of osteosarcoma by inducing mitotic arrest, necrosis and apoptosis, and selective against tumors with high expression of VEGFR2, PDGFRβ and CD31. Based on these results, five osteosarcoma patients who had progressed during NAC were treated with the combination of anlotinib and chemotherapy before surgery, which led to tumor regression in four patients. Next-generation sequencing showed that most patients with tumor reduction expressed medium or high levels of VEGFR2 and PDGFRβ mRNA. The toxicities were tolerable.
In conclusion, osteosarcoma with high expression of VEGFR2, PDGFRβ and CD31 is more sensitive to anlotinib. However, the potential of synergistic effect of anlotinib and chemotherapy in osteosarcoma patients needs further investigation.
本研究旨在利用患者来源的异种移植瘤（PDX）分析安罗替尼的潜在治疗靶点，并评估化疗与安罗替尼联合应用于骨肉瘤患者术前的疗效。
使用43例骨肉瘤标本在小鼠中建立PDX模型，成功建立了21个PDX模型。最终，随机选择6个模型进行药效学实验。将荷瘤小鼠随机分为安罗替尼组（3mg/kg）和安慰剂组（每组n = 5）。治疗后，收获肿瘤并通过免疫组织化学（IHC）和蛋白质印迹法进行分析。
在PDX模型建立过程中，来自复发、转移或化疗耐药供体的肿瘤表现出更高的移植能力。组织学结果表明，安罗替尼通过诱导有丝分裂停滞、坏死和凋亡显著抑制骨肉瘤的生长，并且对VEGFR2、PDGFRβ和CD31高表达的肿瘤具有选择性。基于这些结果，5例在新辅助化疗期间病情进展的骨肉瘤患者在术前接受了安罗替尼与化疗的联合治疗，其中4例患者肿瘤缩小。二代测序显示，大多数肿瘤缩小的患者VEGFR2和PDGFRβ mRNA表达为中高水平。毒性反应可耐受。
总之，VEGFR2、PDGFRβ和CD31高表达的骨肉瘤对安罗替尼更敏感。然而，安罗替尼与化疗在骨肉瘤患者中的协同作用潜力需要进一步研究。
