肿瘤血管靶向治疗的研究进展

肿瘤血管在实体瘤的发生发展中具有重要的作用,靶向肿瘤血管的抑制在抗肿瘤治疗已得到广泛的认同,并生产出大批抗血管制剂,有的已应用于临床治疗.这些新研发的抗血管制剂与传统的针对实体瘤的细胞毒性药物作用机理截然不同.根据作用机理及对血管抑制的阶段不同,肿瘤血管靶向治疗分为抗血管新生制剂和肿瘤血管阻断制剂.抗血管新生制剂旨在抑制肿瘤新生血管新生过程,而肿瘤血管阻断制剂则通过快速而有选择性地损坏或阻塞已构建完成的肿瘤血管,使肿瘤血供受阻引起肿瘤坏死.两者区别主要在作用靶点、肿瘤类型及治疗时机不同.本文对近年来抗血管新生制剂和血管阻断剂的研究进展进行综述.     

抑制肿瘤血管的新生药物

血管新生在肿瘤的生长和侵袭过程中起着关键作用,随着肿瘤血管新生机制研究的深入及以肿瘤血管为靶点的药物在临床治疗肿瘤时取得较好的疗效,证实了通过抑制肿瘤血管新生来抑制肿瘤生长的理念.目前,抗血管新生药物基础和临床研究取得了新的进展,详细了解肿瘤血管新生的分子机制和抗血管新生药物的作用机制将有助于肿瘤的治疗,并为开发新型抗肿瘤药物提供科学依据.     

DLL4在抗肿瘤新生血管治疗中作用的研究进展

抗新生血管治疗是实体肿瘤治疗中的有效策略，近年来抗VEGFA和VEGFR2受体治疗出现了耐药现象。Notch信号转导是一种细胞间信号通路，在肿瘤新生血管生成中起重要作用。在Notch通路中，Delta样配体4（Deltalike ligand 4，DLL4）在影响肿瘤新生血管生成方面起着重要的作用，它能抑制新生血管分支形成，促进新生血管的成熟;阻断DLL4能增加无功能新生血管数量，加剧恶性肿瘤缺血缺氧，抑制肿瘤的生长。对DLL4蛋白的深入研究为肿瘤新生血管分子靶向治疗 提供新的策略和新的靶标，DLL4有可能成为继VEGF后肿瘤血管分子靶向治疗的重要靶点。     

DLLA在抗肿瘤新生血管治疗中作用的研究进展

抗新生血管治疗是实体肿瘤治疗中的有效策略，近年来抗VEGF—A和VEGF—R2受体治疗出现了耐药现象。Notch信号转导是一种细胞问信号通路，在肿瘤新生血管生成中起重要作用。在Notch通路中，Delta样配体4（Delta-likeligand4，DLL4）在影响肿瘤新生血管生成方面起着重要的作用，它能抑制新生血管分支形成，促进新生血管的成熟；阻断DLIA能增加无功能新生血管数量，加剧恶性肿瘤缺血缺氧，抑制肿瘤的生长。对DLIA蛋白的深入研究为肿瘤新生血管分子靶向治疗提供新的策略和新的靶标，DLIA有可能成为继VEGF后肿瘤血管分子靶向治疗的重要靶点。     

肿瘤血管正常化的研究现状

恶性肿瘤的生长和转移依赖邻近的新生血管,有效阻断血管新生是抗肿瘤生长的治疗手段之一.而长期应用抗血管生成药则会导致肿瘤组织耐药,学者们在对该现象深入研究中发现抗血管生成药在抗血管生成的过程中存在逆转肿瘤新生血管、使血管正常化的作用,“肿瘤血管正常化”理论由此提出.全文针对这一理论对其现有的中西医研究尤其是活血药研究进行综述.     

肿瘤新生血管生成抑制药物研究进展

新生血管生成抑制药物可以从不同途径阻断新生血管的生成,达到治疗肿瘤的目的.目前新牛血管生成抑制药物可分为阻断促血管生成因子作用通路的物、直接抑制内皮细胞药物、抑制基底膜降解的药物、抑制细胞整合素的药物、表皮生长因子受体抑制剂和其他种类,有较好的应用前景.     

抗肿瘤新生血管治疗的新进展

血管新生是肿瘤生长、转移的重要条件。在导致肿瘤血管新生的因素中,血管内皮生长因子(vascular endothelialgrowth factor,VEGF)被认为是最重要的因素。抑制VEGF的信号转导有可能抑制血管新生,并进一步抑制肿瘤生长。目前有几种新的可能抑制VEGF信号转导的方法,其中包括基因水平上抑制VEGF及VEGF受体(VEGF receptor,VEGFR)的表达、中和血液循环中的VEGF或VEGFR,以及抑制VEGFR的酪氨酸激酶活性以达到抑制其下游的信号转导等。迄今为止,已报道多种针对VEGF抗血管新生的生物及化学制剂,部分已应用于临床,其他制剂正在进行动物试验或临床试验。本文对抑制VEGF信号转导在抗肿瘤治疗中的研究新进展做一综述。     

VEGF及其在肺癌抗血管生成中的研究进展

临床研究表明,血管内皮生长因子（VEGF）在肺癌血管生长中起着重要作用。肿瘤生长、浸润和转移都依赖于肿瘤血管的生成,而持续表达的VEGF是肿瘤血管生成和肿瘤进展的关键介导因子,通过阻断VEGF信号来抑制血管新生是肿瘤治疗的重要措施之一。     

抗肿瘤血管生成及其联合放化疗的研究进展

抗血管生成治疗肿瘤的理论基础是肿瘤的生长对血管生成的依赖性.新生血管为肿瘤的生长、转移提供氧和营养物质,在无新生血管生成时,实体肿瘤的生长明显被抑制,只局限于原位癌或几百个微米的微转移;而一旦新生血管长入,肿瘤将迅速生长,且浸润和转移的能力大大加强.Folkman把这一现象称为"血管生长切换机制".目前,以抗血管生成为目的的肿瘤治疗策略日益成为国内外关注和研究的焦点,而且在动物试验中已显示出独特的抗肿瘤效应,不过由于肿瘤血管生成的复杂性、异时性及抗肿瘤血管生成疗法自身作用的局限性等原因,其临床疗效并不很理想.于是,人们把目光投向了与传统的放射治疗、化学治疗的联合治疗上.近年来的研究表明,联合治疗具有协同抗肿瘤作用.     

TACE联合抗血管生成药治疗肝癌的研究进展

肝癌是最常见、最致命的恶性肿瘤之一。肝动脉化疗栓塞（transarterial chemoembolization,TACE）是公认的肝癌非手术治疗中最常用的方法之一。TACE在阻断肿瘤组织血供的同时,也增加了肿瘤血管再生及形成侧支循环的风险。新生血管与恶性肿瘤的发生和发展关系密切。抗血管生成药能抑制血管内皮细胞的迁移和增殖,从而抑制肿瘤的生长。本文就TACE联合抗血管生成药治疗肝癌的进展进行综述。     

Circulating endothelial progenitors and tumor resistance to vascular-targeting therapies

Acute mobilization of circulating endothelial progenitors has been implicated in tumor resistance to vascular-disrupting agents. In the current issue of Cancer Discovery, Taylor and colleagues provide novel insight into the kinetics of endothelial progenitor mobilization by vascular-disrupting agents in both mouse tumor models and cancer patients.     

Blood vessel maturation and response to vascular-disrupting therapy in single vascular endothelial growth factor-A isoform-producing tumors

Tubulin-binding vascular-disrupting agents (VDA) are currently in clinical trials for cancer therapy but the factors that influence tumor susceptibility to these agents are poorly understood. We evaluated the consequences of modifying tumor vascular morphology and function on vascular and therapeutic response to combretastatin-A4 3-O-phosphate (CA-4-P), which was chosen as a model VDA. Mouse fibrosarcoma cell lines that are capable of expressing all vascular endothelial growth factor (VEGF) isoforms (control) or only single isoforms of VEGF (VEGF120, VEGF164, or VEGF188) were developed under endogenous VEGF promoter control. Once tumors were established, VEGF isoform expression did not affect growth or blood flow rate. However, VEGF188 was uniquely associated with tumor vascular maturity, resistance to hemorrhage, and resistance to CA-4-P. Pericyte staining was much greater in VEGF188 and control tumors than in VEGF120 and VEGF164 tumors. Vascular volume was highest in VEGF120 and control tumors (CD31 staining) but total vascular length was highest in VEGF188 tumors, reflecting very narrow vessels forming complex vascular networks. I.v. administered 40 kDa FITC-dextran leaked slowly from the vasculature of VEGF188 tumors compared with VEGF120 tumors. Intravital microscopy measurements of vascular length and RBC velocity showed that CA-4-P produced significantly more vascular damage in VEGF120 and VEGF164 tumors than in VEGF188 and control tumors. Importantly, this translated into a similar differential in therapeutic response, as determined by tumor growth delay. Results imply differences in signaling pathways between VEGF isoforms and suggest that VEGF isoforms might be useful in vascular-disrupting cancer therapy to predict tumor susceptibility to VDAs.     

考布他汀A4磷酸酯（CA4P）抗肿瘤作用研究进展

考布他汀A4磷酸酯（combretastatin A4 phosphate,CA4P）是小分子血管破坏剂的代表药物之一,可结合微管蛋白,选择性破坏现存肿瘤血管。其快速特异性阻断肿瘤血管的作用已被众多临床前及临床研究应用多种观测技术所证实。CA4P可致肿瘤组织快速坏死,遗留外周活瘤带,可增强放化疗、免疫疗法、血管生成抑制剂等的抗癌作用。该药目前已进入Ⅲ期临床研究。     

Antiangiogenic agents as second-line therapy for advanced non-small cell lung cancer

With the approval of the antiangiogenic antibody bevacizumab in non-small cell lung cancer (NSCLC) and other malignancies, the tumor vasculature has emerged as a worthwhile therapeutic target. Second-line therapies have the potential to improve overall survival and quality of life over best supportive care alone. Accordingly, phase II and phase III studies are actively evaluating antiangiogenic treatments in the second-line setting in NSCLC, and results are awaited. Such therapies include antiangiogenic antibodies, small molecule inhibitors, and vascular-disrupting agents. This review will present the current landscape of angiogenesis inhibition in NSCLC, focusing on use as second-line therapy.     

Antitumor effect of the vascular-disrupting agent ZD6126 in a murine renal cell carcinoma model

ZD6126 is a vascular-disrupting agent that affects the endothelial tubulin cytoskeleton causing selective occlusion of tumor vasculature and extensive tumor cell necrosis. The present study evaluated the antitumor and antivascular activities of ZD6126 in the clinically relevant murine renal cell carcinoma (RENCA) model and also evaluated biological response to therapy using color Doppler imaging as biomarker. Mice were implanted with RENCA tumor cells (day 0) and established tumors were treated with ZD6126 (100 mg/kg i.p.) or vehicle with repeated intermittent doses on day 10, 14 and 18. ZD6126 treatment led to a significant reduction in tumor size and was associated with extensive tumor necrosis and a reduction in tumor blood flow versus controls. MVD increased with intermittent treatment (day 10, 14 and 18). In an additional study, animals were treated at day 19 and quantitative three-dimensional microvascular corrosion casting was performed to enable detailed assessment of the tumor vascular architecture. Corrosion casting showed that tumor vessel architecture is affected by treatment, whereas pre-existing vessels in control tissues are practically not affected. Inter-vessel and inter-branch distances as well as vessel diameters are influenced by treatment. In conclusion, ZD6126 showed potent antitumor efficacy in the RENCA model and our data suggest that decrease in tumor blood flow may be a useful surrogate marker of treatment effect.     

Vascular-targeted agents for the treatment of angiosarcoma

Purpose

Angiosarcomas are rare, aggressive vascular tumours known to express vascular endothelial growth factor (VEGF), a key pro-angiogenic growth factor. The aim of this study was to determine the potential effects of vascular-targeted agents for the treatment of angiosarcoma, using two human cutaneous angiosarcoma cell lines (ASM and ISO-HAS), and human dermal microvascular endothelial cells (HuDMECs) for comparison.

Methods

Protein arrays were used to assess the expression of angiogenesis-related proteins, and potential drug targets were assessed by ELISA and Western blotting. Response to vascular-targeted agents, including bevacizumab an anti-VEGF antibody, axitinib a VEGF-receptor tyrosine kinase inhibitor, everolimus an mTOR inhibitor, selumetinib a MEK inhibitor and vadimezan a vascular-disrupting agent were compared in functional in vitro cellular assays, including viability, differentiation and migration assays.

Results

ASM and ISO-HAS cells expressed a broad range of pro-angiogenic growth factors. ASM and ISO-HAS VEGF expression was significantly increased (p = 0.029) compared with HuDMECs. Striking responses were seen to vadimezan with an IC₅₀ of 90 and 150 μg/ml for ASM and ISO-HAS cells, respectively. Selumetinib inhibited ASM with an IC₅₀ of 1,750 ng/ml, but was not effective in ISO-HAS. Everolimus reduced both ASM and ISO-HAS viable cell counts by 20 % (p < 0.001). Minimal responses were observed to bevacizumab and axitinib in assays with ASM and ISO-HAS cells.

Conclusions

Further studies are warranted to investigate mTOR inhibitors, MEK inhibitors and vascular-disrupting agents for the treatment of angiosarcoma.     

Preclinical evaluation of vascular-disrupting agents in Ewing’s sarcoma family of tumours

The effects of the tubulin-binding vascular-disrupting agents (VDAs), combretastatin A4 phosphate (CA4P), OXi4503/CA1P and OXi8007, in subcutaneous mouse models of the Ewing’s sarcoma family of tumours (ESFTs) have been investigated alone and in combination with doxorubicin. Delay in subcutaneous tumour growth was observed following treatment of mice with multiple doses of OXi4503/CA1P but not with CA4P or OXi8007. A single dose of OXi4503/CA1P caused complete shutdown of vasculature by 24 h and extensive haemorrhagic necrosis by 48 h. However, a viable rim of proliferating cells remained, which repopulated the tumour within 10 days following the withdrawal of treatment. Combined treatment with doxorubicin 1 h prior to administration of OXi4503/CA1P enhanced the effects of OXi4503/CA1P causing a synergistic delay in tumour growth (p < 0.001). This study demonstrates that OXi4503/CA1P is a potent VDA in ESFT and in combination with conventional cytotoxic agents represents a promising treatment strategy for this tumour group.     

Reversing resistance to vascular-disrupting agents by blocking late mobilization of circulating endothelial progenitor cells

The prevailing concept is that immediate mobilization of bone marrow-derived circulating endothelial progenitor cells (CEP) is a key mechanism mediating tumor resistance to vascular-disrupting agents (VDA). Here, we show that administration of VDA to tumor-bearing mice induces 2 distinct peaks in CEPs: an early, unspecific CEP efflux followed by a late yet more dramatic tumor-specific CEP burst that infiltrates tumors and is recruited to vessels. Combination with antiangiogenic drugs could not disrupt the early peak but completely abrogated the late VDA-induced CEP burst, blunted bone marrow-derived cell recruitment to tumors, and resulted in striking antitumor efficacy, indicating that the late CEP burst might be crucial to tumor recovery after VDA therapy. CEP and circulating endothelial cell kinetics in VDA-treated patients with cancer were remarkably consistent with our preclinical data. These findings expand the current understanding of vasculogenic "rebounds" that may be targeted to improve VDA-based strategies. SIGNIFICANCE: Our findings suggest that resistance to VDA therapy may be strongly mediated by late, rather than early, tumor-specific recruitment of CEPs, the suppression of which resulted in increased VDA-mediated antitumor efficacy. VDA-based therapy might thus be significantly enhanced by combination strategies targeting late CEP mobilization.     

Deoxypodophyllotoxin suppresses tumor vasculature in HUVECs by promoting cytoskeleton remodeling through LKB1-AMPK dependent Rho A activation

Angiogenesis plays a critical role in the growth and metastasis of tumors, which makes it an attractive target for anti-tumor drug development. Deoxypodophyllotoxin (DPT), a natural product isolated from Anthriscus sylvestris, inhibits cell proliferation and migration in various cancer cell types. Our previous studies indicate that DPT possesses both anti-angiogenic and vascular-disrupting activities. Although the RhoA/ RhoA kinase (ROCK) signaling pathway is implicated in DPT-stimulated cytoskeleton remodeling and tumor vasculature suppressing, the detailed mechanisms by which DPT mediates these effects are poorly understood. In the current study, we found that DPT promotes cytoskeleton remodeling in human umbilical vein endothelial cells (HUVECs) via stimulation of AMP-activated protein kinase (AMPK) and that this effect is abolished by either treatment with a selective AMPK inhibitor or knockdown. Moreover, the cellular levels of LKB1, a kinase upstream of AMPK, were enhanced following DPT exposure. DPT-induced activation of AMPK in tumor vasculature effect was also verified by transgenic zebrafish (VEGFR2:GFP), Matrigel plug assay, and xenograft model in nude mice. The present findings may lay the groundwork for a novel therapeutic approach in treating cancer.     

Recent advances in squamous non-small cell lung cancer: evidence beyond predictive biomarkers

Squamous non-small cell lung cancer (NSCLC) has always been characterized by a limited number of therapeutic options and by the lack of actionable biomarkers compared to its non-squamous counterpart. Recent clinical trials have led to the approval of new anti-neoplastic drugs available to both non-squamous and squamous NSCLC, consisting in a vascular-disrupting agent and two immune check-point inhibitors; additionally, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR) is currently under evaluation by the Food and Drug Administration (FDA). While predictive molecular biomarkers have not been identified with consistency and are still highly demanded, these agents proved themselves noteworthy and can be considered a powerful addition to the available treatments for squamous NSCLC.