Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA.
AAPS J. 2012 Sep;14(3):500-9. doi: 10.1208/s12248-012-9363-4. Epub 2012 May 1.
Vascular endothelial growth factor (VEGF) is a key mediator of angiogenesis, whose effect on cancer growth and development is well characterized. Alternative splicing of VEGF leads to several different isoforms, which are differentially expressed in various tumor types and have distinct functions in tumor blood vessel formation. Many cancer therapies aim to inhibit angiogenesis by targeting VEGF and preventing intracellular signaling leading to tumor vascularization; however, the effects of targeting specific VEGF isoforms have received little attention in the clinical setting. In this work, we investigate the effects of selectively targeting a single VEGF isoform, as compared with inhibiting all isoforms. We utilize a molecular-detailed whole-body compartment model of VEGF transport and kinetics in the presence of breast tumor. The model includes two major VEGF isoforms, VEGF(121) and VEGF(165), receptors VEGFR1 and VEGFR2, and co-receptors Neuropilin-1 and Neuropilin-2. We utilize the model to predict the concentrations of free VEGF, the number of VEGF/VEGFR2 complexes (considered to be pro-angiogenic), and the receptor occupancy profiles following inhibition of VEGF using isoform-specific anti-VEGF agents. We predict that targeting VEGF(121) leads to a 54% and 84% reduction in free VEGF in tumors that secrete both VEGF isoforms or tumors that overexpress VEGF(121), respectively. Additionally, 21% of the VEGFR2 molecules in the blood are ligated following inhibition of VEGF(121), compared with 88% when both isoforms are targeted. Targeting VEGF(121) reduces tumor free VEGF and is an effective treatment strategy. Our results provide a basis for clinical investigation of isoform-specific anti-VEGF agents.
血管内皮生长因子（VEGF）是血管生成的关键介质，其对癌症生长和发展的影响已得到充分证实。VEGF 的选择性剪接导致了几种不同的亚型，这些亚型在不同的肿瘤类型中表达不同，并在肿瘤血管形成中具有不同的功能。许多癌症治疗方法旨在通过靶向 VEGF 并阻止导致肿瘤血管化的细胞内信号传导来抑制血管生成；然而，在临床环境中，针对特定 VEGF 亚型的作用受到的关注较少。在这项工作中，我们研究了与抑制所有亚型相比，选择性靶向单个 VEGF 亚型的效果。我们利用存在乳腺癌的 VEGF 转运和动力学的分子详细全身隔室模型。该模型包括两种主要的 VEGF 亚型，VEGF(121)和 VEGF(165)，受体 VEGFR1 和 VEGFR2，以及共受体 Neuropilin-1 和 Neuropilin-2。我们利用该模型预测了使用针对特定 VEGF 的抗 VEGF 药物抑制 VEGF 后，游离 VEGF 的浓度、被认为具有促血管生成作用的 VEGF/VEGFR2 复合物的数量以及受体占有率谱。我们预测，针对两种 VEGF 亚型均分泌或 VEGF(121)过表达的肿瘤，靶向 VEGF(121)可使肿瘤中游离 VEGF 减少 54%和 84%。此外，抑制 VEGF(121)后，血液中有 21%的 VEGFR2 分子被配体化，而靶向两种亚型时则有 88%被配体化。靶向 VEGF(121)可降低肿瘤中的游离 VEGF，是一种有效的治疗策略。我们的结果为针对特定 VEGF 亚型的抗 VEGF 药物的临床研究提供了依据。
