恶性胶质瘤靶向治疗研究进展

目的 恶性胶质瘤是一种最常见的原发恶性脑肿瘤,是癌症治疗中最具挑战性疾病之一.因为手术切除后肿瘤易复发和治疗抵抗性,患者预后普遍较差.胶质瘤的分子靶向治疗正逐渐引起广泛关注.本研究总结恶性胶质瘤发病相关的分子病理改变和靶向药物的临床应用与研究进展.方法 采用PubMed文献检索系统,以“恶性胶质瘤”和“分子靶向治疗”为关键词,检索2007-01-01-2015-12-31的相关文献.纳入标准:(1)与恶性胶质瘤分子靶向通路相关的文献;(2)与恶性胶质瘤抗血管生成治疗相关的文献;(3)与恶性胶质瘤分子靶向药物的Ⅰ期及Ⅱ期临床研究相关的文献;(4)与恶性胶质瘤分子靶向耐药相关的文献.根据纳入标准分析文献43篇.结果 胶质瘤靶向治疗方向主要集中在RTK/RAS/PI3K通路、促血管生成通路和一些其他重要的细胞内信号转导通路.然而,一些因素如信号通路之间的串扰、瘤内异质性和胶质瘤干细胞的治疗抵抗性限制了单一药物的活性.各种分子靶向药物单药治疗未能表现出更好的生存获益,还需与其他治疗方法联合应用.目前对于恶性胶质瘤患者多靶点激酶抑制剂治疗的研究还处于起始阶段.结论 分子靶向药物在恶性胶质瘤的治疗中具有重要临床意义和应用潜力,但由于胶质瘤的复杂的分子生物学特性,分子靶向治疗面临诸多挑战,还需进一步探索与研究.     

雷公藤甲素抗胶质瘤作用分子机制的研究进展

多形性胶质母细胞瘤的发生与发展中存在多个信号转导通路的异常,包括Rb信号通路、P53信号通路、MAPK信号通路、P13K信号通路和细胞凋亡信号通路等。近期研究发现雷公藤甲素能够靶向恶性胶质瘤细胞中的多种异常通路,抑制胶质瘤细胞的增殖并诱导凋亡。本文将对胶质瘤细胞中的信号转导通路的异常以及雷公藤甲素靶向治疗胶质瘤的研究进展进行综述。     

恶性胶质瘤分子靶向药物联合治疗新动态

恶性胶质瘤是原发脑肿瘤中最常见的类型,但传统的治疗方法对改善生存作用有限。针对肿瘤细胞内传导通路上特异分子的靶向治疗是近年的研究热点,但单一分子靶向药物治疗的效果并不十分理想,客观有效率不超过10%～15%。因此,人们寄希望于采用联合靶向治疗多个信号传导通路或者同一通路上的不同靶点和靶向药物与传统的化放疗联合等治疗策略来改善疗效。本文总结近几年来恶性胶质瘤分子靶向药物联合治疗方面的新动态,其中部分研究已获得令人鼓舞的初步试验数据。     

恶性黑色素瘤的靶向治疗

目前恶性黑色素瘤(MM)主要的靶向治疗方法包括信号传导通路抑制剂、靶向凋亡、蛋白酶体抑制剂、抗血管生成治疗等.MM靶向治疗研究的发展方向是根据患者对靶向治疗敏感性的差异选择更加个体化的靶向治疗方法和技术.     

恶性胶质瘤中的EGFR-STAT3信号通路

表皮生长因子受体-信号转导和转录激活因子3(EGFR-STAT3)信号通路与恶性胶质瘤的发生、发展密切相关,EGFR可通过JAK依赖和非依赖两种途径活化STAT3,激活下游基因转录。以EGFR-STAT3为靶点的分子靶向治疗是近年来的研究热点,有望为恶性胶质瘤的治疗带来新的希望。     

胶质瘤干细胞及相关的信号转导通路

胶质瘤干细胞(glioma stem cells,GSC)是近年来在胶质瘤组织中发现的肿瘤干细胞。GSC具有自我更新和分化的能力,可以通过不断分化产生新的肿瘤;对GSC标志物的鉴定有助于胶质瘤恶性程度的诊断。GSC的起源目前仍不明确,成熟的神经胶质细胞、限制性神经祖细胞以及神经干细胞均可能为GSC的前体。推测如Wnt、Notch、SHH、BMI1、PTEN等信号通路活跃在GSC中,一些新的治疗手段通过作用于GSC的信号转导通路可靶向治疗胶质瘤。深入研究GSC的起源、标志物以及相关信号转导通路,可为胶质瘤治疗提供新的策略。     

HGF/c-MET信号通路抑制剂在抗胰腺癌中的研究进展

胰腺癌是恶性程度较高的肿瘤之一.靶向治疗日渐成为胰腺癌治疗的重要组成部分.研究证实肝细胞生长因子及其受体(HGF/c-MET)信号通路在胰腺癌发生、发展过程中起重要作用,通过抑制该条信号通路能够起到显著的抗胰腺癌作用.因此,HGF/c-MET靶向抑制剂的研究为胰腺癌的治疗开辟了一条新的途径.     

胶质瘤干细胞及其相关信号通路的研究进展

胶质瘤是颅内常见的原发肿瘤,高级别的胶质瘤治疗效果不佳,对放化疗抵抗.目前认为在胶质瘤组织中存在着胶质瘤干细胞,此种细胞具有自我更新和分化的能力,是高级别胶质瘤放化疗失败的主要原因,针对胶质瘤干细胞的靶向治疗可能相对于传统放化疗能更好地改善高级别胶质瘤的预后.一些新的治疗手段通过作用于胶质瘤干细胞信号通路可靶向治疗胶质瘤.     

联合用药靶向胶质母细胞瘤样干细胞的治疗进展

胶质母细胞瘤作为常见的恶性胶质瘤,其等级系数高,致死性强.随着肿瘤干细胞理论的提出,为肿瘤靶向治疗提供了新的途径.通过联合用药抑制生长机制,阻止胶质母细胞瘤样干细胞的增殖,从而为靶向治疗恶性胶质瘤提供了可能.本文就联合用药靶向胶质母细胞瘤样干细胞进行简要综述.     

Wnt信号调控胶质瘤或胶质瘤干细胞增殖及迁移作用的研究进展

近年研究发现Wnt信号通路与神经胶质瘤及其肿瘤干细胞的细胞增殖及细胞迁移相关,Wnt信号蛋白及其关键家族成员的表达水平与胶质瘤恶性程度密切有关,提示Wnt信号及相关通路的靶干预可能成为恶性胶质瘤治疗的新途径.     

The Challenges and the Promise of Molecular Targeted Therapy in Malignant Gliomas

Malignant gliomas are the most common malignant primary brain tumors and one of the most challenging forms of cancers to treat. Despite advances in conventional treatment, the outcome for patients remains almost universally fatal. This poor prognosis is due to therapeutic resistance and tumor recurrence after surgical removal. However, over the past decade, molecular targeted therapy has held the promise of transforming the care of malignant glioma patients. Significant progress in understanding the molecular pathology of gliomagenesis and maintenance of the malignant phenotypes will open opportunities to rationally develop new molecular targeted therapy options. Recently, therapeutic strategies have focused on targeting pro-growth signaling mediated by receptor tyrosine kinase/RAS/phosphatidylinositol 3-kinase pathway, proangiogenic pathways, and several other vital intracellular signaling networks, such as proteasome and histone deacetylase. However, several factors such as cross-talk between the altered pathways, intratumoral molecular heterogeneity, and therapeutic resistance of glioma stem cells (GSCs) have limited the activity of single agents. Efforts are ongoing to study in depth the complex molecular biology of glioma, develop novel regimens targeting GSCs, and identify biomarkers to stratify patients with the individualized molecular targeted therapy. Here, we review the molecular alterations relevant to the pathology of malignant glioma, review current advances in clinical targeted trials, and discuss the challenges, controversies, and future directions of molecular targeted therapy.Abbreviations: BBB, blood-brain barrier; CDK4, cyclin-dependent kinase 4; CDKN2A, cyclin-dependent kinase inhibitor 2A; c-KIT, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog; EGFR, epidermal growth factor receptor; FT, farnesyl transferase; FTI, FT inhibitor; GBMs, glioblastomas; GSCs, glioma stem cells; HDAC, histone deacetylase; IDH, isocitrate dehydrogenase; MAPK, mitogen-activated protein kinase; MGMT, O⁶-methylguanine DNA methyltransferase; miRNAs, microRNAs; mTOR, mammalian target of rapamycin; OS, overall survival; PDGFR, PDGF receptor; PFS, progression-free survival; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; RB1, retinoblastoma susceptibility protein 1; RTK, receptor tyrosine kinase; SHH, sonic hedgehog; TCGA, The Cancer Genome Atlas; TKIs, receptor tyrosine kinase inhibitors; TMZ, temozolomide; VEGF, vascular endothelial growth factor     

Endogenous inhibitors of angiogenesis in malignant gliomas: nature's antiangiogenic therapy

Angiogenesis is necessary for tumor growth beyond a volume of approximately 2 mm(3). This observation, along with the accessibility of tumor vessels to therapeutic targeting, has resulted in a research focus on inhibitors of angiogenesis. A number of endogenous inhibitors of angiogenesis are found in the body. Some of these are synthesized by specific cells in different organs, and others are created by extracellular proteolytic cleavage of plasma-derived or extracellular matrix-localized proteins. In this review, we focus on angiostatin, endostatin, PEX, pigment epithelial-derived factor, and thrombospondin (TSP)-1 and -2, either because these molecules are expressed in malignant glioma biopsies or because animal studies in malignant glioma models have suggested that their therapeutic administration could be efficacious. We review the known mechanisms of action, potential receptors, expression in glioma biopsy samples, and studies testing their potential therapeutic efficacy in animal models of malignant glioma. Two conclusions can be made regarding the mechanisms of action of these inhibitors: (1) Several of these inhibitors appear to mediate their antiangiogenic effect through multiple protein-protein interactions that inhibit the function of proangiogenic molecules rather than through a specific receptor-mediated signaling event, and (2) TSP-1 and TSP-2 appear to mediate their antiangiogenic effect, at least in part, through a specific receptor, CD36, which initiates the antiangiogenic signal. Although not proven in gliomas, evidence suggests that expression of specific endogenous inhibitors of angiogenesis in certain organs may be part of a host antitumor response. The studies reviewed here suggest that new antiangiogenic therapies for malignant gliomas offer exciting promise as nontoxic, growth-inhibitory agents.     

Local intracerebral delivery of endogenous inhibitors by osmotic minipumps effectively suppresses glioma growth in vivo

The systemic administration of endogenous inhibitors significantly reduced the growth of human glioma in vivo, but required the production of a large amount of biologically active protein. In this study we reduced the amount of protein needed and optimized the therapeutical response by delivering the endogenous inhibitors locally into the brain by osmotic minipumps. Human hemopexin fragment of MMP-2 or COOH-terminal fragment of platelet factor-4 were delivered locally and continuously into the brain of mice implanted intracranially with glioma cells, by osmotic minipumps connected to an intracranial catheter. Local delivery of human hemopexin fragment of MMP-2 and COOH-terminal fragment of platelet factor-4 significantly inhibited the growth of well-established malignant glioma in nude and BALB/C mice. When the inhibitors were given at the same concentration, the efficacy of the local delivery was much higher than that reached with the systemic administration, both when the inhibitor was administered daily or continuously by s.c. minipumps. Moreover, the local delivery reduced the amount of protein needed to reach a significant therapeutic response. Intracerebral delivery maintained a long-term control of glioma growth and inhibited glioma recurrence in a surgical resection model. Treatment showed no side effects. Histochemical analysis of tumors showed that the tumor growth inhibition was the result of a decrease in tumor vasculature and a change in tumor vessel morphology. Our data demonstrate that local intracerebral delivery of endogenous inhibitors effectively inhibits malignant glioma growth and reduces the amount of protein needed to reach a therapeutical response.     

Terminally sialylated and fucosylated complex N-glycans are involved in the malignant behavior of high-grade glioma

Gliomas are the most common intracranial primary tumors, for which very few therapeutic options are available. The most malignant subtype is the glioblastoma, a disease associated with a 5-year survival rate lower than 5%. Given that research in glycobiology continues highlighting the role of glycans in tumor cell biology, it offers an interesting niche for the search of new therapeutic targets. In this study, we characterized aberrant glycosylation and its impact on cell biology over a broad panel of high- and low-grade glioma cell lines. Results show high expression of terminal Lewis glycans, mainly SLe^x, and overexpression of sialyl- and fucosyltransferases involved in their biosynthesis in high-grade glioma cell lines. Moreover, we report an association of complex multi-antennary N-glycans presenting β1,6-GlcNAc branches with the high-grade glioma cells, which also overexpressed the gene responsible for these assemblies, MGAT5. In addition, downmodulation of N-glycosylation by treatment with the inhibitors Tunicamycin/Swainsonine or MGAT5 silencing decreased SLe^x expression, adhesion and migration in high-grade glioma cells. In contrast, no significant changes in these cell capacities were observed in low-grade glioma after treatment with the N-glycosylation inhibitors. Furthermore, inhibition of histone deacetylases by Trichostatin A provoked an increase in the expression of SLe^x and its biosynthetic related glycosyltransferases in low-grade glioma cells. Our results describe that aggressive glioma cells show high expression of Lewis glycans anchored to complex multi-antennary N-glycans. This glycophenotype plays a key role in malignant cell behavior and is regulated by histone acetylation dependent mechanisms.     

Adenoviral (full-length) Apo2L/TRAIL gene transfer is an ineffective treatment strategy for malignant glioma

Death ligand-mediated apoptosis is a promising strategy of gene therapy for human malignant glioma. We here report that the infection of human malignant glioma cell lines with an adenoviral vector encoding full length human Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Ad-Apo2L/TRAIL) results in strong Apo2L/TRAIL transgene expression and the release of full-length Apo2L/TRAIL into the cell culture medium. However, Ad-Apo2L/TRAIL is a poor inducer of cell death, even in the presence of inhibitors of protein synthesis, in human glioma cell lines which are sensitive to soluble recombinant human His-tagged Apo2L/TRAIL (amino acids 114–281). Moreover, Ad-Apo2L/TRAIL gene transfer inhibits soluble His-tagged Apo2L/TRAIL-induced apoptosis, strongly suggesting that the adenovirally encoded full-length Apo2L/TRAIL is not a suitable molecule for glioma cancer gene therapy. This study has important implications for the future development of therapeutic strategies aiming at death receptor activation in refractory cancers such as malignant glioma.     

ErbB receptor tyrosine kinase network inhibition radiosensitizes carcinoma cells

PURPOSE: The expression of epidermal growth factor receptor (EGFR)-CD533, a truncation mutant of the wild-type EGFR, radiosensitizes carcinoma and malignant glioma cell lines. This deletion mutant disrupts EGFR activation and downstream signaling through the formation of inhibitory dimerizations. In this study, the effects of EGFR-CD533 on other ErbB receptor tyrosine kinase (RTK) family members were quantified to better understand the mechanism of EGFR-CD533-mediated radiosensitization. METHODS AND MATERIALS: Breast carcinoma cell lines with different ErbB RTK expression profiles were transduced with EGFR or ErbB2 deletion mutants (EGFR-CD533 and ErbB2-CD572) using an adenoviral vector. ErbB RTK activation, mitogen activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)/p70S6K signaling, and clonogenic survival were determined for expression of each deletion mutant. RESULTS: EGFR-CD533 radiosensitizes carcinoma cells with either high EGFR expression (MDA-MB231) or low EGFR expression (T47D) through significant blockade of the ErbB RTK network. Analysis of clonogenic survival demonstrate significant enhancement of the alpha/beta ratios, as determined by the linear-quadratic model. Split-dose survival experiments confirm that EGFR-CD533 reduces the repair of cellular damage after ionizing radiation. CONCLUSION: Expression of EGFR-CD533 inhibits the ErbB RTK network and radiosensitizes carcinoma cells irrespective of the ErbB RTK expression patterns, and ErbB2-CD572 does not radiosensitize cells with low EGFR expression. These studies demonstrate that the mechanism of action for EGFR-CD533-mediated radiosensitization is inhibition of the ErbB RTK network, and is an advantage for radiosensitizing multiple malignant cell types.     

The potential of RECK inducers as antitumor agents for glioma

Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a tumor and metastasis suppressor gene, is critical for the regulation of the invasive and metastatic activities of tumor cells. RECK is down-regulated in some malignancies and its expression is positively correlated with survival of patients with cancer. Patients with malignant glioma have poor prognosis. Since RECK expression decreases as the tumor stage progresses from less invasive grade II glioma to invasive glioblastoma multiforme, up-regulation of RECK by natural or synthetic agents might be a valuable therapeutic option for glioma. Histone deacetylase inhibitors and non-steroidal anti-inflammatory drugs have been widely used clinically and demonstrated to increase RECK expression in cancer cells, thus they might be used as RECK inducers. In this article, the functions of RECK and the role of RECK in glioma are reviewed, with emphasis on the potential application of RECK inducers in the treatment of glioma.     

Inhibition of autophagy at a late stage enhances imatinib‐induced cytotoxicity in human malignant glioma cells

Malignant gliomas are common primary tumors of the central nervous system. The prognosis of patients with malignant glioma is poor in spite of current intensive therapy and thus novel therapeutic modalities are necessary. Imatinib mesylate, a tyrosine kinase inhibitor, is effective in the therapy of tumors including leukemias but not as a monotherapy for malignant glioma. Recently, it is thought that the adequate modulation of autophagy can enhance efficacy of anticancer therapy. The outcome of autophagy manipulation, however, seems to depend on the autophagy initiator, the combined stimuli, the extent of cellular damage and the type of cells, and it is not yet fully understood how we should modulate autophagy to augment efficacy of each anticancer therapy. In this study, we examined the effect of imatinib with or without different types of autophagy inhibitors on human malignant glioma cells. Imatinib inhibited the viability of U87‐MG and U373‐MG cells in a dose dependent manner and caused nonapoptotic autophagic cell death. Suppression of imatinib‐induced autophagy by 3‐methyladenine or small interfering RNA against Atg5, which inhibit autophagy at an early stage, attenuated the imatinib‐induced cytotoxicity. In contrast, inhibition of autophagy at a late stage by bafilomycin A1 or RTA 203 enhanced imatinib‐induced cytotoxicity through the induction of apoptosis following mitochondrial disruption. Our findings suggest that therapeutic efficiency of imatinib for malignant glioma may be augmented by inhibition of autophagy at a late stage, and that appropriate modulation of autophagy may sensitize tumor cells to anticancer therapy. © 2008 Wiley‐Liss, Inc.     

人参皂甙与IL-2协同诱导PBMC对恶性脑胶质瘤细胞杀伤活性研究

目的：探索提高恶性脑胶质瘤治疗效果的新途径。方法：用人参皂甙（ｇｉｎｓｅｎｏｓｉｄｅ,ＧＳ）与白细胞介素２（ＩＬ－２）协同诱导人外周血单个核细胞（ＰＢＭＣ）制成ＧＳ－ＬＡＫ细胞,用ＭＴＴ法测定其对恶性脑胶质瘤细胞（ＢＴ３２５）的杀伤活性,并与ＬＡＫ细胞相比较。结果：效应细胞ＧＳ－ＬＡＫ在增殖数量和杀伤恶性脑胶质瘤细胞活性等方面均优于ＬＡＫ细胞,且ＩＬ－２用量减少。结论：采用ＧＳ－ＬＡＫ细胞,可提高效应细胞的数量和活性,为恶性脑胶质瘤的免疫治疗打下了理论基础。