VEGF as a potential target in lung cancer

Introduction The vascular endothelial growth factor A (VEGF) is the main mediator of angiogenesis. In addition, VEGF contributes to cancer growth and metastasis directly targeting tumor cells. VEGF overexpression and/or high VEGF serum levels have been reported in lung cancer.

Areas covered We searched Pubmed for relevant preclinical studies with the terms ‘lung cancer’ ‘VEGF’ and ‘in vivo’. We also searched the Clinicaltrials.gov database, the FDA and the EMA websites for the most recent updates on clinical development of anti-VEGF agents.

Expert opinion VEGF plays an important role in sustaining the development and progression of lung cancer and it might represent an attractive target for therapeutic strategies. Nevertheless, clinical trials failed to attend the promising expectations deriving from preclinical studies with anti-VEGF agents. To improve the efficacy of anti-VEGF therapies in lung cancer, potential strategies might be the employment of combinatory therapies with immune checkpoint inhibitors or agents that inhibit signaling pathways and proangiogenic factors activated in response to VEGF blockade, and the identification of novel targets in the VEGF cascade. Finally, the identification of predictive markers might help to select patients who are more likely to respond to anti-angiogenic drugs.     

Pharmacokinetics of intravitreal anti-VEGF drugs in vitrectomized versus non-vitrectomized eyes

Introduction: The review aims to discuss effects of vitrectomy on pharmacokinetics of anti-vascular endothelial growth factor (anti-VEGF) agents, and attempt to provide treatment guidance.

Areas covered: An Embase search was conducted using the terms ‘anti-VEGF’, ‘pegaptanib’, ‘ranibizumab’, ‘bevacizumab’, ‘aflibercept’, ‘pharmacokinetics’, ‘half-life’, ‘clearance’, ‘metabolism’, ‘vitrectomy’, ‘vitrectomized’. Published data regarding the pharmacokinetic properties of the above drugs and the effect of vitrectomy in animal and human eyes was reviewed.

Expert opinion: There are limited studies on the effect of vitrectomy on pharmacokinetic properties of anti-VEGF drugs in human eyes. Most animal models indicate that intravitreal drugs have reduced half-lives and increased clearance in vitrectomized eyes. More studies, with carefully selected design, are required to explore this further. However, considering existing evidence, it is important to consider vitreous and lens status when monitoring and treating patients. Authors recommend fixed monthly dosing, with low threshold for increasing frequency of injection even to 2-weekly if required, as well as close monitoring of patients to establish individual response. There may be an increased role for slow-release steroid implants in vitrectomized eyes with DME or RVO. Longer acting substances currently under development such as brolucizumab or abicipar pegol, may become the treatment of choice in the future.     

玻璃体腔注射抗血管内皮生长因子药物相关并发症分析

自从抗血管内皮生长因子(vascular endothelial growth factor,VEGF)的药物问世后,其在眼病中的应用日益增多,疗效也得到广泛认可。但随着该药物的广泛使用,相应的并发症和不良反应包括眼部不良反应和全身不良反应也逐渐被发现和报道。随着抗VEGF药物进入国家医保目录,其临床使用量必将大幅度增加。为了更好的使用药物以及处理并发症,我们复习近年相关文献,分析玻璃体腔内注射抗VEGF药物的相关并发症,供临床参考。     

康柏西普对RVO继发黄斑水肿患者黄斑区视网膜血管密度的影响

目的：评价视网膜静脉阻塞(RVO)继发黄斑水肿抗血管内皮生长因子(VEGF)治疗前后黄斑区视网膜血管密度的变化。

方法：回顾性病例对照研究。选取2018-04/06临床确诊为RVO继发黄斑水肿患者23例,给予玻璃体腔注射0.5mg/0.05mL康柏西普。对比治疗前后BCVA以及行OCTA检查,软件自动识别及测量治疗前后CMT和浅层视网膜毛细血管网血管长度密度和灌注密度的变化。

结果：随访时间为1mo,治疗后BCVA较治疗前提高(P<0.05),CMT较治疗前降低(P<0.05),治疗后浅层视网膜毛细血管网中位于中心凹、旁中心凹及总区域的血管长度密度和灌注密度与治疗前均无差异(P>0.05)。

结论：单次抗VEGF治疗RVO继发黄斑水肿在短期内BCVA和CMT明显好转,并且未加重黄斑缺血。     

Potent anti-angiogenesis and anti-tumor activity of a nove human anti-VEGF antibody,MIL60

Angiogenesis is crucial for tumor development, growth and metastasis. Vascular endothelial growth factor （VEGF） has been implicated in promoting solid tumor growth and metastasis via stimulating tumor-associated angiogenesis, and blocking the activity of VEGF can starve tumors. Avastin, which is a humanized anti-VEGF antibody, has been successfully applied in clinics since 2004. However, the price of Avastin is extremely high for Chinese people. Here, we report a novel human anti-VEGF neutralizing antibody, MIL60, which shows an affinity comparable to that of Avastin （the KD value of MIL60 was 44.5 pM, while that of Avastin was 42.7 pM）. MIL60 displays favorable actions in inhibiting VEGF-triggered endothelial cell proliferation （the IC5o value of M IL60 was 31-6.4 ng/ml and that of Avastin was 47--.8.1 ng/ml）, migration （8 pg/ml or 0.8 pg/ml MIL60 versusthe control： P〈O.05） and tube formation （2 I~g/ml or 0.2 lzg/ml MIL60 versusthe control： P〈O.05） viathe VEGFR2 signaling pathway. Moreover, MIL60 was shown to inhibit tumor growth and angiogenesis in vivo in xenograft models of human colon carcinoma and ovarian cancer using immunotherapy and immunohistochemistry analysis （MIL60 versus N.S.： P=0.0007; Avastin versus N.S.： P=0.00046）. These data suggest that MIL60 is a potential therapeutic, anti-angiogenic agent. Our work provides a novel anti-VEGF antibody, which can be considered an anti-tumor antibody candidate and a new option for patients with various cancers.     

Combination of AIBP,apoA-I,and Aflibercept Overcomes Anti-VEGF Resistance in Neovascular AMD by Inhibiting Arteriolar Choroidal Neovascularization

PurposeAnti-VEGF resistance represents a major unmet clinical need in the management of choroidal neovascularization (CNV). We have previously reported that a combination of AIBP, apoA-I, and an anti-VEGF antibody overcomes anti-VEGF resistance in laser-induced CNV in old mice in prevention experiments. The purpose of this work is to conduct a more clinically relevant study to assess the efficacy of the combination of AIBP, apoA-I, and aflibercept in the treatment of anti-VEGF resistance of experimental CNV at different time points after laser photocoagulation.MethodsTo understand the pathobiology of anti-VEGF resistance, we performed comprehensive examinations of the vascular morphology of laser-induced CNV in young mice that are highly responsive to anti-VEGF treatment, and in old mice that are resistant to anti-VEGF therapy by indocyanine green angiography (ICGA), fluorescein angiography (FA), optical coherence tomography (OCT), and Alexa 568 isolectin labeled choroid flatmounts. We examined the efficacy of the combination therapy of AIBP, apoA-I, and aflibercept intravitreally delivered at 2, 4, and 7 days after laser photocoagulation in the treatment of CNV in old mice.ResultsLaser-induced CNV in young and old mice exhibited cardinal features of capillary and arteriolar CNV, respectively. The combination therapy and the aflibercept monotherapy were equally effective in treating capillary CNV in young mice. In old mice, the combination therapy was effective in treating anti-VEGF resistance by potently inhibiting arteriolar CNV, whereas aflibercept monotherapy was ineffective.ConclusionsCombination therapy of AIBP, apoA-I, and aflibercept overcomes anti-VEGF resistance in experimental CNV in old mice by inhibiting arteriolar CNV.     

早产儿视网膜病变抗VEGF治疗后复发的危险因素分析

目的：探讨早产儿视网膜病变(ROP)抗VEGF治疗后复发的危险因素。

方法：回顾性分析2016-06/2019-10在我院行抗VEGF治疗的ROP患儿56例的临床资料,根据首次抗VEGF治疗后ROP复发情况分为复发组(8例)和非复发组(48 例)。比较两组患儿出生体质量、孕周、血小板体积及是否患有贫血、凝血障碍、败血症、支气管肺发育不良、新生儿呼吸窘迫综合征、窒息、肺炎、颅内出血、卵圆孔未闭、动脉导管未闭等情况,分析抗VEGF治疗后ROP复发的危险因素。

结果：两组患儿出生体质量和出生后颅内出血发生情况有明显差异,Logistic回归分析结果显示,出生低体质量(OR=9.800,P=0.039)和颅内出血(OR=17.571,P=0.002)均是抗VEGF治疗后ROP复发的危险因素。

结论：出生低体质量(<1 000g)和患有颅内出血是抗VEGF治疗后ROP复发的危险因素。     

Objective optical quality and visual outcomes after the PresbyMAX monocular ablation profile

AIM: To identify proangiogenic factors engaged in neovascular age-related macular degeneration (AMD) except vascular endothelial growth factor (VEGF) from human retinal pigment epithelial cells (hRPE) and investigate the underlying mechanisms. METHODS: VEGF receptor 2 (VEGFR2) in ARPE-19 cells was depleted by siRNA transfection or overexpressed through adenovirus infection. The mRNA and the protein levels of interleukin-8 (IL-8) in ARPE-19 cells were measured by quantitative real-time PCR and ELISA assay respectively. The protein levels of AKT, p-AKT, MEK, p-MEK, ERK1/2, p-ERK1/2, JNK, p-JNK, p38 and p-p38 were detected by western blotting. A selective chemical inhibitor, LY3214996, was employed to inhibit phosphorylation of ERK1/2. Cell viability was determined by MTT assay. RESULTS: Knockdown of VEGFR2 in ARPE-19 cells robustly augmented IL-8 production at both the mRNA and the protein levels. Silencing VEGFR2 substantially enhanced phosphorylation of MEK and ERK1/2 while exerted no effects on phosphorylation of AKT, JNK and p38. Inhibiting ERK1/2 phosphorylation by LY3214996 reversed changes in VEGFR2 knockdown-induced IL-8 upregulation at the mRNA and the protein levels with no effects on cell viability. VEGFR2 overexpression significantly reduced IL-8 generation at the mRNA and the protein levels. CONCLUSION: Blockade of VEGF signaling augments IL-8 secretion via MEK/ERK1/2 axis and overactivation of VEGF pathway decreases IL-8 production in hRPE cells. Upregulated IL-8 expression after VEGF signaling inhibition in hRPE cells may be responsible for being incompletely responsive to anti-VEGF remedy in neovascular AMD, and IL-8 may serve as an alternative therapeutic target for neovascular AMD.