血管内皮生长因子及其受体靶向治疗在胆道恶性肿瘤中的研究进展
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1.内蒙古医科大学研究生院,内蒙古 呼和浩特 010050;2.内蒙古医科大学附属医院 肝胆胰脾外科,内蒙古 呼和浩特 010050

作者简介:

杨阳,内蒙古医科大学研究生院硕士研究生,主要从事肝胆胰外科疾病方面的研究。

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Progress in targeted therapy against vascular endothelial growth factors and their receptors for biliary tract cancers
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1.Graduate School, Inner Mongolia Medical University, Hohhot 010050, China;2.Department of Hepatobiliary Pancreatic and Splenic Surgery, the Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, China

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    摘要:

    胆道恶性肿瘤(BTC)根据解剖部位分为胆囊癌、肝内胆管癌、肝外胆管癌,其发病隐匿、早期诊断困难,患者预后差,手术治疗作为唯一可以根治的治疗方式效果却不理想,化疗对于此类患者效果较差且安全性难以保证。靶向治疗是近年来新兴的治疗手段,可以靶向针对患者肿瘤细胞中的特定位点,在疗效、安全性方面都比传统治疗手段有较大幅度的提升。血管内皮生长因子及其受体是多种实体肿瘤中表达的抗肿瘤靶点之一,在BTC中也有较高水平的表达。二者相互结合后,通过多条信号传导通路将生物学信号传入细胞内进而调控肿瘤的血管生成、血管转移。针对血管内皮生长因子及其受体的靶向治疗在BTC中已有一定成效。贝伐珠单抗是第一种应用于临床的血管内皮生长因子抑制剂,其联合以吉西他滨为基础的系统化疗方案、免疫检查点抑制剂(ICI)或酪氨酸激酶抑制剂(TKI)都在BTC中收获了较好的效果,但部分仍未达预期,需更多临床试验进一步探索。雷莫卢单抗是一种血管内皮生长因子受体抑制剂,在BTC中研究较少,目前只在联合系统化疗、ICI方面有一定应用。而针对血管内皮生长因子及其受体的TKI目前种类繁多,如仑伐替尼、索拉非尼、阿帕替尼、安罗替尼。仑伐替尼无疑是当前肝胆系统恶性肿瘤中研究的重点,作为一种多靶点TKI,仑伐替尼联合ICI和系统化疗在BTC患者中取得了令人鼓舞的疗效,在大幅度改善患者预后的同时安全性也得到了保障。这为未来的综合治疗手段指明了方向。其他TKI如安罗替尼、阿帕替尼在BTC中也有较为广泛的应用。多种靶向药物在BTC中已开展了广泛的临床研究,其中不乏某些药物为单一靶点抑制剂,这便提示临床工作者,在给予患者靶向药物前,应充分考虑到患者体内目标靶点的表达情况,这样才能做到精准治疗、精确治疗,最大程度提升治疗效果。未来的研究应以精准治疗和系统治疗并重,以改善患者生存、提高其生活质量为唯一目的。

    Abstract:

    Biliary tract cancers (BTC) are classified according to anatomical sites into gallbladder cancer, intrahepatic bile duct cancer, and extrahepatic bile duct cancer. Their onset is insidious, early diagnosis is difficult, and the prognosis for patients is poor. Surgical treatment, as the only curative treatment method, is not ideal in its effectiveness. Chemotherapy is less effective and its safety is difficult to guarantee for such patients. Targeted therapy has emerged in recent years as a novel treatment modality, targeting specific sites in tumor cells of patients, with significant improvements in both efficacy and safety compared to traditional treatment methods. Vascular endothelial growth factors and their receptors are among the targeted anti-tumor sites expressed in various solid tumors, including BTC, at relatively high levels. When combined, they transmit biological signals into cells through multiple signaling pathways, thereby regulating tumor angiogenesis and hematogenous metastasis. Targeted therapy against vascular endothelial growth factors and their receptors has achieved certain success in BTC. Bevacizumab is the first vascular endothelial growth factor inhibitor used in clinical practice, and its combination with gemcitabine-based systemic chemotherapy, immune checkpoint inhibitors, or tyrosine kinase inhibitors has shown promising results in BTC, although some outcomes have not met expectations, necessitating further clinical trials. Ramucirumab, a vascular endothelial growth factor receptor inhibitor, has been less studied in BTC and is currently only applied in combination with systemic chemotherapy and immune checkpoint inhibitors. Currently, there are various types of tyrosine kinase inhibitors targeting vascular endothelial growth factor and its receptor, such as lenvatinib, sorafenib, apatinib, and anlotinib. Lenvatinib is undoubtedly a focus of research in malignant tumors of the hepatobiliary system. As a multi-target tyrosine kinase inhibitor, lenvatinib combined with immune checkpoint inhibitors and systemic chemotherapy has achieved encouraging efficacy in BTC patients, while ensuring safety to a significant extent. This indicates the direction for future comprehensive treatment methods. Other tyrosine kinase inhibitors such as anlotinib and apatinib also have widely used in BTC. Various targeted drugs have been extensively studied in BTC, and some of them are single-target inhibitors. This suggests to clinical practitioners the importance of fully considering the expression of target sites in patients before administering targeted drugs, in order to achieve precise and maximum therapeutic effects. Future research should focus on both precision treatment and systemic therapy, with the sole goal of improving patient survival and enhancing their quality of life.

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杨阳,王万祥.血管内皮生长因子及其受体靶向治疗在胆道恶性肿瘤中的研究进展[J].中国普通外科杂志,2024,33(2):265-272.
DOI:10.7659/j. issn.1005-6947.2024.02.013

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  • 收稿日期:2023-11-08
  • 最后修改日期:2024-01-18
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  • 在线发布日期: 2024-03-09