Antiangiogenic Therapy in Clear Cell Renal Carcinoma (CCRC): Pharmacological Basis and Clinical Results.
Antiangiogenic Therapy in Clear Cell Renal Carcinoma (CCRC): Pharmacological Basis and Clinical Results.
复制标题
肾透明细胞癌的抗血管生成治疗：药理学基础和临床结果。
DOI：
10.3390/cancers13235896
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发表时间：
2021-11-24
期刊：
影响因子：
5.2
通讯作者：
Tucci M
中科院分区：
文献类型：
--
作者：
Comandone A;Vana F;Comandone T;Tucci M
在过去的15年中，有关肿瘤细胞发生和进展的生物学机制的知识的深刻进步导致了转移性透明细胞肾癌治疗前景的巨大变化。如今，已知新血管生成在肿瘤生长和转移扩散中起关键作用。特别是，冯希佩尔-林道（VHL）肿瘤抑制基因的突变，导致通过多种促血管生成因子的转录血管生成的关键作用，是清楚地认识到。基于这一生物学证据，三类具有抗血管生成活性的靶向疗法已获得批准用于治疗晚期疾病：酪氨酸激酶抑制剂（TKI）;干扰血管内皮生长因子（VEGF）的单克隆抗体;以及两种哺乳动物雷帕霉素靶点（mTOR）抑制剂。这些药物在无进展生存期和客观缓解率方面显示出令人印象深刻的结果。此外，由于肾细胞癌的免疫原性特征以及血管生成和免疫监视系统之间的相互作用的最新信息，最近开始了“第二次治疗革命”。因此，免疫检查点抑制剂单独或与TKI联合使用已获得批准。本文综述了近年来被批准用于治疗转移性肾透明细胞癌的抗血管生成药物的药理学特征和活性。血管生成对肿瘤的生长、复制、侵袭和转移具有直接的刺激作用。传统的肾细胞癌的一个重要部分是血管生成依赖性肿瘤和支持这一进程的途径已在过去20年进行了彻底的研究。因此，许多酪氨酸激酶抑制剂（TKI）（舒尼替尼、索拉非尼、帕唑帕尼、阿西替尼和卡博替尼），一种单克隆抗体（贝伐单抗）和两种哺乳动物雷帕霉素靶标（mTOR）抑制剂（替西罗莫司和依维莫司）已被研究并批准用于治疗晚期或转移性透明细胞肾癌在一线以及二线治疗中，与先前可用的疗法或安慰剂相比，在无进展生存期和客观反应率方面具有令人印象深刻的结果。最近，一种新型药物已被批准用于转移性CCRC：免疫调节检查点抑制剂（ICI），单独使用或与TKI联合使用。然而，关于肾透明细胞癌（CCRC）治疗，仍有许多问题和领域有待探索：预测生物标志物的研究，最佳患者选择，如何克服耐药机制，以及日常临床实践中的最佳治疗顺序。本文综述了该类药物的药理学特性和抗肿瘤活性。这些疗法的毒性和临床局限性也进行了讨论。
In the last 15 years, a deep improvement in the knowledge regarding the biological mechanisms responsible for neoplastic cell development and progression has led to a dramatic change in the treatment landscape of metastatic clear cell renal carcinoma. Nowadays, it is known that neo-angiogenesis is a key player in tumor growth and metastatic spread. In particular, the crucial role of the mutation of the von Hippel–Lindau (VHL) tumor suppressor gene, leading to angiogenesis through the transcription of multiple pro-angiogenic factors, is clearly recognized. On the basis of this biological evidence, three classes of targeted therapies with antiangiogenetic activity have received approval for the treatment of advanced disease: tyrosine kinase inhibitors (TKIs); a monoclonal antibody that interferes with vascular endothelial growth factor (VEGF); and two mammalian target of rapamycin (mTOR) inhibitors. These drugs showed impressive results in terms of progression-free survival and objective response rate. In addition, a “second therapeutic revolution” has recently started, due to the latest information on the immunogenic characteristics of renal cell carcinoma and the interplay between angiogenesis and immune surveillance systems. Consequently, immune checkpoint inhibitors, alone or in combination with TKIs, have been approved. In this review, we analyze the pharmacological characteristics and activity of antiangiogenic drugs approved for the treatment of metastatic clear cell renal carcinoma. Angiogenesis has a direct stimulatory effect on tumor growth, duplication, invasion and metastatic development. A significant portion of conventional renal cell carcinomas are angiogenesis-dependent tumors and the pathways supporting this process have been thoroughly investigated over the last 20 years. As a consequence, many tyrosine kinase inhibitors (TKIs) (sunitinib, sorafenib, pazopanib, axitinib, and cabozantinib), one monoclonal antibody (bevacizumab), and two mammalian target of rapamycin (mTOR) inhibitors (temsirolimus and everolimus) have been investigated and approved for the treatment of advanced or metastatic clear cell renal carcinoma (metastatic CCRC) in first-line, as well as second-line, therapy, with impressive results in progression-free survival and in the objective response rate compared with previously available therapies or placebo. Recently, a new type of drug has been approved for metastatic CCRC: immunomodulatory checkpoint inhibitors (ICIs), alone or in combination with TKIs. However, many questions and areas to be explored still remain with regard to clear cell renal carcinoma (CCRC) treatment: research on predictive biomarkers, the best patient selection, how to overcome the mechanisms of resistance, and the best sequence of therapies in daily clinical practice. This review focuses on the pharmacological properties and anticancer activities of these drugs. The toxicity profile and clinical limitations of these therapies are also discussed.
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影响因子：
2.2
作者：
Bose A;Lowe DB;Rao A;Storkus WJ
通讯作者：
Storkus WJ
影响因子：
45.3
作者：
Escudier, Bernard;Eisen, Tim;Bukowski, Ronald M.
通讯作者：
Bukowski, Ronald M.
影响因子：
168.9
作者：
Escudier, Bernard;Pluzanska, Anna;Moore, Nicola
通讯作者：
Moore, Nicola
影响因子：
7.3
作者：
Guertin, David A.;Sabatini, David M.
通讯作者：
Sabatini, David M.
DOI：
10.1016/j.ejca.2018.02.012
发表时间：
2018-05
期刊：
European journal of cancer (Oxford, England : 1990)
影响因子：
--
作者：
Choueiri TK;Hessel C;Halabi S;Sanford B;Michaelson MD;Hahn O;Walsh M;Olencki T;Picus J;Small EJ;Dakhil S;Feldman DR;Mangeshkar M;Scheffold C;George D;Morris MJ
通讯作者：
Morris MJ