转移性结直肠癌抗血管生成靶向治疗的研究进展

近年来,由于各种新的化疗药物及分子靶向药物的使用,转移性结直肠癌(metastatic colorectal cancer,m CRC)的个体化治疗逐步取得了重要的成果。研究表明,抗血管生成靶向药物与化疗药物的联合使用作为转移性结直肠癌的一线治疗方案,可明显改善治疗效果,延长患者的生存时间。血管内皮生长因子(vascularendothelial growth factor,VEGF)是肿瘤血管生成过程中最主要的因子。贝伐单抗是通过基因工程技术得到的针对血管内皮生长因子-A(VEGF-A)的单克隆抗体,作为抗血管生成靶向药物用于转移性结直肠癌的临床治疗。本文对近年来转移性结直肠癌的抗血管生成靶向治疗,尤其是贝伐单抗治疗的相关研究进展进行综述并展望未来抗血管生成靶向治疗的发展前景。     

低剂量化疗联合中药抗血管生成作用的研究进展

自从八十年代初Folkman提出肿瘤生长依赖于新血管生成的理论,抗血管生成治疗已逐渐成为肿瘤研究的热点和肿瘤治疗的新策略。对抗血管生成治疗的深入研究也使人们对许多细胞毒化疗药物的功能活性有了新的审视,近期一些国外研究表明降低化疗药物的剂量可特异地杀伤新生肿瘤血管内皮细胞,利用化疗药物的这一新靶点,采取合理的给药方式和计划,可能帮助解决常规高剂量化疗引起的毒副作用和耐药性的难题。我国传统的中医药在肿瘤诊治上已经积累了许多宝贵的经验,对这些初步筛选出采的抗肿瘤中药借助现代技术进行精细分析、模拟修饰和药理机制研究,发现我国传统中药提取物中许多有效成分显示出了抗血管生成作用,将其与低剂量化疗联合应用也显示出良好抑瘤效果,同时毒副作用小,患者生存质量提高,因此这种联合疗法为晚期肿瘤患者提供了一种新的安全有效的治疗途径,本文对目前低剂量化疗与中药联合应用的抗肿瘤血管生成机制及应用前景作一综述。     

PD-L1和VEGF双靶点联合阻断治疗的研究进展

免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)通过阻断负调控免疫信号激活宿主抗肿瘤免疫反应。临床试验表明,ICIs的治疗能够明显引起部分晚期癌症患者的肿瘤消退。在临床实践中,ICIs治疗的一个主要问题是药物应答率低。尽管PD-L1表达、错配修复缺陷、肿瘤浸润性淋巴细胞状态等多种预测生物标志物已被用于筛选对治疗有应答的患者,但ICIs单药治疗的耐药性仍存在。近期研究表明,联合抗VEGF治疗可以减轻ICIs的耐药性。VEGF能抑制肿瘤生长和转移所必需的血管生成,同时能够对肿瘤免疫微环境进行重编程,减轻ICIs的耐药性。目前已针对此双靶点的联合治疗开展了很多临床试验,并获得了令人振奋的结果。对抗PD-L1联合抗VEGF治疗的作用机制以及PD-L1/VEGF联合阻断治疗的临床研究进行了综述汇总。     

CCL5/CCR5生物学轴在肿瘤中作用的研究进展

肿瘤因其易转移、易复发的特性成为一大难以治愈的疾病,已严重威胁到人类的生命健康。肿瘤微环境在肿瘤的生长、迁移、免疫逃逸、血管生成等过程中具有明显的促进作用。肿瘤微环境中细胞分泌的CCL5发挥的作用已受到越来越多的关注,且许多研究表明抑制CCL5/CCR5生物学轴可抑制肿瘤迁移、血管生成等,预示着这可能成为一个新的肿瘤治疗策略。本文总结了近年来关于CCL5/CCR5生物学轴的研究,包括CCL5/CCR5生物学轴介导的肿瘤生长迁移、血管生成、免疫逃逸等作用,及CCR5抑制剂在肿瘤治疗中的广阔前景。     

抑制血管生成治疗肿瘤的策略和展望

新生血管生成是绝大多数肿瘤得以生长和转移的必要前提。所以 ,通过抑制肿瘤血管生成来抑制肿瘤是非常有前途的一种方法 ,有望发展成为一种新型的癌症疗法。主要可以分为两大类 :一是通过抑制促血管生成信号或扩大抑制血管生成因子的作用来干扰肿瘤新生血管的形成过程 ,这领域的广泛研究已经发现了一系列促血管生成因子及其抑制剂和血管生成抑制因子 ;二是利用肿瘤血管与正常血管的差别来携带杀伤性药物直接特异性破坏已形成的肿瘤血管 ;另外 ,内皮细胞及其前体细胞制成疫苗也可起到直接杀伤作用。到目前为止 ,虽然很多抑制肿瘤血管的药物已经被用于临床试验 ,但结果往往不尽如人意 ,从长远来看 ,需要更有效的治疗方法。包括抗血管基因治疗策略 ,靶向药物导入系统的研究 ,以及抗血管生成药物和免疫疗法、化疗和放射治疗的联合应用都在探讨中。随着肿瘤模型评估系统的发展 ,抗血管治疗肿瘤的方法在不久的将来一定会广泛进入临床应用。     

抗血管生成药物联合化疗治疗进展期非小细胞肺癌研究现状

大部分非小细胞肺癌患者需要进行系统化疗。研究表明以铂类药物为基础的标准一线系统化疗联合贝伐单抗能一定程度改善晚期非小细胞肺癌患者的预后。另有一些研究对多靶点抗血管生成的酪氨酸激酶抑制剂(如:索拉非尼,舒尼替尼,西地尼布,凡德他尼等)联合标准化疗的疗效进行了评估,为非小细胞肺癌患者提供了更多的治疗策略。本文主要对抗血管生成药物联合细胞毒性化疗药物治疗非小细胞肺癌的临床研究进行系统回顾。     

贝伐珠单抗在肿瘤治疗中的应用研究进展

贝伐珠单抗是一种重组人源化免疫球蛋白 G1 单克隆抗体,可通过抑制血管内皮生长因子活性及抗血管生成,达到抑制肿瘤生长 的目的,目前已广泛用于结直肠癌、肺癌、卵巢癌等多种肿瘤的治疗,尤其是通过与基础化疗结合,能显著提高治疗的有效率以及延长 肿瘤患者的无进展生存期和总生存期。综述贝伐珠单抗的抗肿瘤作用机制、在不同肿瘤治疗中的应用、用于肿瘤治疗时机与疗效差异以 及不良反应和防治。     

抗血管生成药物联合化疗治疗进展期非小细胞肺癌研究现状

大部分非小细胞肺癌患者需要进行系统化疗.研究表明以铂类药物为基础的标准一线系统化疗联合贝伐单抗能一定程度改善晚期非小细胞肺癌患者的预后.另有一些研究对多靶点抗血管生成的酪氨酸激酶抑制剂(如:索拉非尼,舒尼替尼,西地尼布,凡德他尼等)联合标准化疗的疗效进行了评估,为非小细胞肺癌患者提供了更多的治疗策略.本文主要对抗血管生成药物联合细胞毒性化疗药物治疗非小细胞肺癌的临床研究进行系统回顾.     

以VEGF及VEGFR2为靶位的抗肿瘤血管生成主动免疫治疗的研究进展

肿瘤细胞通过刺激新生血管生成来满足对营养及供氧的不断增长的需求,因此,肿瘤组织生长对于新生血管形成的依赖性使得抗血肿瘤管生成已经成为肿瘤学基础研究与临床治疗领域中最吸引人的策略之一.在众多的促血管生成因子中,血管内皮生长因子(VEGF)及其受体VEGFR2(鼠和人中也分别称为Flk-1和KDR)对于与肿瘤生长、转移及复发相关的血管生成是至关重要的.此外,通过打破肿瘤组织自身介导的免疫耐受与逃避,主动免疫治疗已成为一种崭新的抗肿瘤治疗方法.通过将这两种策略联合应用,抗血管生成主动免疫治疗使得更加有效地抑制肿瘤血管生成成为可能.这种免疫治疗与抗血管生成的联合应用有望成为一种有良好前景的研究方案.本文总结了通过打破VEGF/VEGFR2信号通路实现的抗肿瘤血管生成主动免疫治疗方面最新研究进展.本文讨论了旨在抑制血管生成的三种不同形式的抗肿瘤疫苗-细胞疫苗、蛋白质/多肽疫苗及基因/DNA疫苗,以及这一领域未来的研究方向.     

美国新批准一种乳腺癌药物

美国食品和药物管理局日前发布新闻公报,批准一种由美国基因技术研究公司生产的名为“阿瓦斯汀”（AVASTIN）的药物用于治疗乳腺癌。该药是一种抗血管生成的药物,它通过抑制血管内皮生长因子发挥作用来阻断对肿瘤的血液供应,使肿瘤无法在体内扩散,并能使化疗有效发挥作用。此前,这种药物已被美国药管局批准用于治疗肺癌、结肠癌和直肠癌,并在欧洲获准用于治疗乳腺癌。     

Angiogenesis in gynecological cancers and the options for anti-angiogenesis therapy

Angiogenesis is required in cancer, including gynecological cancers, for the growth of primary tumors and secondary metastases. Development of anti-angiogenesis therapy in gynecological cancers and improvement of its efficacy have been a major focus of fundamental and clinical research. However, survival benefits of current anti-angiogenic agents, such as bevacizumab, in patients with gynecological cancer, are modest. Therefore, a better understanding of angiogenesis and the tumor microenvironment in gynecological cancers is urgently needed to develop more effective anti-angiogenic therapies, either or not in combination with other therapeutic approaches. We describe the molecular aspects of (tumor) blood vessel formation and the tumor microenvironment and provide an extensive clinical overview of current anti-angiogenic therapies for gynecological cancers. We discuss the different phenotypes of angiogenic endothelial cells as potential therapeutic targets, strategies aimed at intervention in their metabolism, and approaches targeting their (inflammatory) tumor microenvironment.     

Tumor microenvironment abnormalities: causes, consequences, and strategies to normalize

A solid tumor is an organ-like entity comprised of neoplastic cells and non-transformed host stromal cells embedded in an extracellular matrix. The expression of various genes is influenced by interactions among these cells, surrounding matrix, and their local physical and biochemical microenvironment. The products encoded by these genes, in turn, control the pathophysiological characteristics of the tumor, and give rise to the abnormal organization, structure, and function of tumor blood vessels. These abnormalities contribute to heterogeneous blood flow, vascular permeability, and microenvironment. Proliferating tumor cells produce solid stress which compresses blood and lymphatic vessels. As a result of vessel leakiness and lack of functional lymphatics, interstitial fluid pressure is significantly elevated in solid tumors. Each of these abnormalities forms a physiological barrier to the delivery of therapeutic agents to tumors. Furthermore, the metabolic microenvironment in tumors such as hypoxia and acidosis hinder the efficacy of anti-tumor treatments such as radiation therapy and chemotherapy. A judicious application of anti-angiogenic therapy has the potential to overcome these problems by normalizing the tumor vessels and making them more efficient for delivery of oxygen and drugs. Combined anti-angiogenic and conventional therapies have shown promise in the clinic.     

The quest for surrogate markers of angiogenesis: a paradigm for translational research in tumor angiogenesis and anti-angiogenesis trials

Inhibition of tumor angiogenesis suppresses tumor growth and metastatic spreading in many experimental models, suggesting that anti-angiogenic drugs may be used to treat human cancer. During the past decade more than eighty molecules that showed anti-angiogenic activity in preclinical studies were tested in clinical cancer trials, but most of them failed to demonstrate any measurable anti-tumor activity and none have been approved for clinical use. Recent results stemming from trials with anti-VEGF antibodies, used alone or in combination with chemotherapy, suggest that systemic anti-angiogenic therapy may indeed have a measurable impact on cancer progression and patient survival. From the clinical studies it became nevertheless clear that the classical endpoints used in anti-cancer trials do not bring sufficient discriminative power to monitor the effects of anti-angiogenic drugs. It is therefore necessary to identify and validate molecular, cellular and functional surrogate markers of angiogenesis to monitor activity and efficacy of anti-angiogenic drugs in patients. Availability of such markers will be instrumental to re-evaluate the role of tumor angiogenesis in human cancer, to identify new molecular targets and drugs, and to improve planning, monitoring and interpretation of future studies. Future anti-angiogenesis trials integrating biological endpoints and surrogate markers or angiogenesis will require close collaboration between clinical investigators and laboratory-based researchers.     

卟啉金属有机骨架材料在肿瘤治疗中的应用

目前,恶性肿瘤严重威胁人类健康和生命。临床上常用放疗法和化疗法治疗肿瘤,在一定程度上抑制肿瘤的生长和转移。但是,传统的化疗药物在给药过程中缺乏靶向性、副作用大,而且大多数化疗药物水溶性差,效果有限,高剂量的重复给药会导致耐药,单一模式的治疗策略效果不佳。因此通过构建靶向智能多功能纳米载药系统实现肿瘤精准诊断和治疗成为近年来的研究热点。卟啉金属有机骨架（MOFs）材料具有多孔性、大比表面积、表面可修饰等特性,有望成为良好的靶向刺激响应型药物载体。而且卟啉MOFs可以避免卟啉分子的自聚集以及在激发态的自猝灭,还具有卟啉分子的宽光谱响应范围,是一类具有广阔应用前景的固体光敏剂,因此卟啉MOFs近年来成为构建靶向智能多功能纳米载药系统的重要平台。本论文综述了近年来基于卟啉金属有机骨架材料的肿瘤治疗策略,特别是基于肿瘤内源性组分（pH、酶、氧化还原）和外源性物理信号（声、磁、光）刺激触发的多功能纳米平台用于肿瘤精准诊断和治疗的最新研究进展,并讨论了卟啉MOFs在未来肿瘤治疗中面临的挑战和机遇。     

Vessel abnormalization: another hallmark of cancer? Molecular mechanisms and therapeutic implications

As a result of excessive production of angiogenic molecules, tumor vessels become abnormal in structure and function. By impairing oxygen delivery, abnormal vessels fuel a vicious cycle of non-productive angiogenesis, which creates a hostile microenvironment from where tumor cells escape through leaky vessels and which renders tumors less responsive to chemoradiation. While anti-angiogenic strategies focused on inhibiting new vessel growth and destroying pre-existing vessels, clinical studies showed modest anti-tumor effects. For many solid tumors, anti-VEGF treatment offers greater clinical benefit when combined with chemotherapy. This is partly due to a normalization of the tumor vasculature, which improves cytotoxic drug delivery and efficacy and offers unprecedented opportunities for anti-cancer treatment. Here, we overview key novel molecular players that induce vessel normalization.     

Cytosolic PhospholipaseA2 Inhibition with PLA-695 Radiosensitizes Tumors in Lung Cancer Animal Models

Lung cancer remains the leading cause of cancer deaths in the United States and the rest of the world. The advent of molecularly directed therapies holds promise for improvement in therapeutic efficacy. Cytosolic phospholipase A2 (cPLA₂) is associated with tumor progression and radioresistance in mouse tumor models. Utilizing the cPLA₂ specific inhibitor PLA-695, we determined if cPLA2 inhibition radiosensitizes non small cell lung cancer (NSCLC) cells and tumors. Treatment with PLA-695 attenuated radiation induced increases of phospho-ERK and phospho-Akt in endothelial cells. NSCLC cells (LLC and A549) co-cultured with endothelial cells (bEND3 and HUVEC) and pre-treated with PLA-695 showed radiosensitization. PLA-695 in combination with irradiation (IR) significantly reduced migration and proliferation in endothelial cells (HUVEC & bEND3) and induced cell death and attenuated invasion by tumor cells (LLC &A549). In a heterotopic tumor model, the combination of PLA-695 and radiation delayed growth in both LLC and A549 tumors. LLC and A549 tumors treated with a combination of PLA-695 and radiation displayed reduced tumor vasculature. In a dorsal skin fold model of LLC tumors, inhibition of cPLA₂ in combination with radiation led to enhanced destruction of tumor blood vessels. The anti-angiogenic effects of PLA-695 and its enhancement of the efficacy of radiotherapy in mouse models of NSCLC suggest that clinical trials for its capacity to improve radiotherapy outcomes are warranted.     

用于肿瘤治疗的免疫检查点抑制剂相关预测生物标志物的研究进展

恶性肿瘤是严重威胁人类健康和社会发展的疾病。传统的肿瘤治疗方法如手术、放疗、化疗和靶向治疗等不能完全满足临床治疗的需求,新兴的免疫治疗成为了肿瘤治疗领域的研究热点。免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)作为一种肿瘤免疫治疗方法,已获批用于治疗多种肿瘤,如肺癌、肝癌、胃癌和结直肠癌等。然而,ICIs在临床使用过程中,只有少数患者会出现持久反应,一些患者还会出现耐药和不良反应。因此,预测生物标志物的鉴定和开发对提高ICIs的治疗效果至关重要。肿瘤ICIs预测生物标志物主要包括肿瘤生物标志物、肿瘤微环境生物标志物、循环相关生物标志物、宿主环境生物标志物以及组合生物标志物等,对患者筛查、个体化治疗和预后评估具有重要意义。本文就肿瘤ICIs治疗预测生物标志物的前沿进展作一综述。     

Rapid Copper Acquisition by Developing Murine Mesothelioma: Decreasing Bioavailable Copper Slows Tumor Growth,Normalizes Vessels and Promotes T Cell Infiltration

Copper, an essential trace element acquired through nutrition, is an important co-factor for pro-angiogenic factors including vascular endothelial growth factor (VEGF). Decreasing bioavailable copper has been used as an anti-angiogenic and anti-cancer strategy with promising results. However, the role of copper and its potential as a therapy in mesothelioma is not yet well understood. Therefore, we monitored copper levels in progressing murine mesothelioma tumors and analyzed the effects of lowering bioavailable copper. Copper levels in tumors and organs were assayed using atomic absorption spectrophotometry. Mesothelioma tumors rapidly sequestered copper at early stages of development, the copper was then dispersed throughout growing tumor tissues. These data imply that copper uptake may play an important role in early tumor development. Lowering bioavailable copper using the copper chelators, penicillamine, trientine or tetrathiomolybdate, slowed in vivo mesothelioma growth but did not provide any cures similar to using cisplatin chemotherapy or anti-VEGF receptor antibody therapy. The impact of copper lowering on tumor blood vessels and tumor infiltrating T cells was measured using flow cytometry and confocal microscopy. Copper lowering was associated with reduced tumor vessel diameter, reduced endothelial cell proliferation (reduced Ki67 expression) and lower surface ICAM/CD54 expression implying reduced endothelial cell activation, in a process similar to endothelial normalization. Copper lowering was also associated with a CD4⁺ T cell infiltrate. In conclusion, these data suggest copper lowering is a potentially useful anti-mesothelioma treatment strategy that slows tumor growth to provide a window of opportunity for inclusion of other treatment modalities to improve patient outcomes.     

Combined Anti-Angiogenic Therapy Targeting PDGF and VEGF Receptors Lowers the Interstitial Fluid Pressure in a Murine Experimental Carcinoma

Elevation of the interstitial fluid pressure (IFP) of carcinoma is an obstacle in treatment of tumors by chemotherapy and correlates with poor drug uptake. Previous studies have shown that treatment with inhibitors of platelet-derived growth factor (PDGF) or vascular endothelial growth factor (VEGF) signaling lowers the IFP of tumors and improve chemotherapy. In this study, we investigated whether the combination of PDGFR and VEGFR inhibitors could further reduce the IFP of KAT-4 human carcinoma tumors. The tumor IFP was measured using the wick-in-needle technique. The combination of STI571 and PTK/ZK gave an additive effect on the lowering of the IFP of KAT-4 tumors, but the timing of the treatment was crucial. The lowering of IFP following combination therapy was accompanied by vascular remodeling and decreased vascular leakiness. The effects of the inhibitors on the therapeutic efficiency of Taxol were investigated. Whereas the anti-PDGF and anti-VEGF treatment did not significantly inhibit tumor growth, the inhibitors enhanced the effect of chemotherapy. Despite having an additive effect in decreasing tumor IFP, the combination therapy did not further enhance the effect of chemotherapy. Simultaneous targeting of VEGFR and PDGFR kinase activity may be a useful strategy to decrease tumor IFP, but the timing of the inhibitors should be carefully determined.