Lauricella Eleonora, Mandriani Barbara, Cavallo Federica, Pezzicoli Gaetano, Chaoul Nada, Porta Camillo, Cives Mauro
Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy.
Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, Bari, Italy.
Front Oncol. 2022 Aug 17;12:957068. doi: 10.3389/fonc.2022.957068. eCollection 2022.
Neuroendocrine neoplasms (NENs) are highly vascularized malignancies arising from cells of the diffuse neuroendocrine system. An intricated cross-talk exists between NEN cells and the tumor microenvironment, and three main molecular circuits (VEGF/VEGFR pathway, FGF-dependent signaling and PDGF/PDGFR axis) have been shown to regulate angiogenesis in these neoplasms. Multiple randomized trials have investigated antiangiogenic agents over the past two decades, and sunitinib is currently approved for the treatment of advanced, progressive, G1/G2 pancreatic NENs. In recent years, two phase III clinical trials have demonstrated the efficacy and safety of surufatinib, a multi-tyrosine kinase angioimmune inhibitor, in patients with well-differentiated pancreatic and extrapancreatic NENs, and two studies of this agent are currently underway in Europe and US. The HIF-2α inhibitor belzutifan has recently received regulatory approval for the treatment of tumors arising in the context of Von-Hippel Lindau syndrome including pancreatic NENs, and a study of this drug in patients with sporadic tumors is presently ongoing. Combinations of antiangiogenic agents with chemotherapeutics and targeted drugs have been tested, with accumulating toxicities being a matter of concern. The potential of antiangiogenic agents in fine-tuning the immune microenvironment of NENs to enhance the activity of immune checkpoint inhibitors has been only partially elucidated, and further research should be carried out at this regard. Here, we review the current understanding of the biology of angiogenesis in NENs and provide a summary of the latest clinical investigations on antiangiogenic drugs in this malignancy.
神经内分泌肿瘤（NENs）是起源于弥漫性神经内分泌系统细胞的高度血管化恶性肿瘤。NEN细胞与肿瘤微环境之间存在复杂的相互作用，并且已证明三个主要分子回路（VEGF/VEGFR途径、FGF依赖性信号传导和PDGF/PDGFR轴）调节这些肿瘤中的血管生成。在过去二十年中，多项随机试验研究了抗血管生成药物，舒尼替尼目前被批准用于治疗晚期、进展性G1/G2胰腺NENs。近年来，两项III期临床试验证明了多酪氨酸激酶血管免疫抑制剂索凡替尼在分化良好的胰腺和胰腺外NENs患者中的疗效和安全性，目前欧洲和美国正在对该药物进行两项研究。HIF-2α抑制剂贝佐蒂凡最近已获得监管批准，用于治疗包括胰腺NENs在内的与冯·希佩尔-林道综合征相关的肿瘤，目前正在对散发性肿瘤患者进行该药物的研究。抗血管生成药物与化疗药物和靶向药物的联合应用已得到测试，累积毒性是一个值得关注的问题。抗血管生成药物在微调NENs免疫微环境以增强免疫检查点抑制剂活性方面的潜力仅得到部分阐明，在这方面应进一步开展研究。在此，我们综述了目前对NENs血管生成生物学的理解，并总结了该恶性肿瘤中抗血管生成药物的最新临床研究情况。
