CDK4/6抑制剂在治疗脑胶质母细胞瘤中的研究进展

细胞周期素依赖性蛋白激酶在临床上已用于乳腺癌的治疗,其机制是促使抑癌基因Rb磷酸化,使细胞从G1期进入S期。CDK4/6抑制剂可以抑制乳腺癌、头颈癌、非小细胞肺癌等多种恶性肿瘤的活性。胶质母细胞瘤具有复发率高、生存期短、预后差等特点,治疗难度大,而CDK4/6理论上作为胶质母细胞瘤(GBM)治疗的靶点,CDK4/6抑制剂作用于cyclin D-CDK4/6-INK4-Rb通路,也同样可以抑制胶质母细胞瘤。作为有希望治疗胶质母细胞瘤药物,CDK4/6抑制剂在动物实验,肿瘤细胞系等研究中展示了大量的证据证明其对胶质母细胞瘤能产生抑制作用。同时CDK4/6抑制剂其研发方向是寻找预测标志物,探索联合治疗,以试图解决神经胶质母细胞瘤治疗中的耐药性和复发性中的关键问题,为治疗神经胶质瘤的研究提供新方向和思路。     

靶向清除胶质瘤干细胞在胶质母细胞瘤治疗方面的应用前景

胶质母细胞瘤(Glioblastomas,GBMs;WHOⅣ级)是最致命的人类肿瘤之一,因其富集血管和弥漫浸润性生长,使得手术不能全切除,易在切除的肿瘤残腔周围复发。胶质母细胞瘤高度不均一性,分为三个等级,最高级的是肿瘤干细胞,位于     

血管生成拟态在胶质母细胞瘤中的研究进展

血管生成拟态(vasculogenic mimicry,VM)指的是高度侵袭性和基因上失分化的肿瘤细胞形成的运输液体的管道结构。VM有两种类型。管道型VM在形态上与内皮细胞衬覆的血管非常相似;图案样基质型VM是由富含基质蛋白的细胞外基质形成的中空的、能够运输液体的网络状结构,并与肿瘤血管相吻合。VM与恶性肿瘤的侵袭、转移以及患者的预后有密切的相关关系。已有研究分别证实胶质母细胞瘤中同样存在两种类型的VM,但是,其胶质瘤中的vM是否存在特异性的标记物、调控机制、与干细胞的联系等,尚需进一步的研究。现就VM在胶质瘤的研究进展、其与肿瘤干细胞的关系作一综述。     

老年胶质母细胞瘤治疗研究进展

老年胶质母细胞瘤(glioblastoma multiform,GBM)的治疗方案尚未达成一致的共识,是目前研究的热点。在安全范围内手术全切肿瘤可改善老年GBM的预后。放疗能够延长老年GBM患者的生存期,短程低分割放疗能达到标准放疗的治疗效果,且毒副作用较小。O~6-甲基鸟嘌呤-DNA-甲基转移酶(O~6-methylguanine-DNA methyltransferase,MGMT)启动子甲基化状态在老年GBM患者中能预测替莫唑胺(temozolomide,TMZ)化疗的疗效,对于MGMT启动子甲基化的老年GBM患者,TMZ化疗能够明显延长生存期。对于一般状况较好的老年GBM患者,TMZ联合低分割放疗较单一低分割放疗能延长生存期。在临床工作中,面对老年GBM患者,需结合患者的功能状态、合并症、肿瘤分子病理特征、社会支持等综合因素制定个体化的治疗方案。     

整合素抑制剂Cilengitide治疗多形性胶质母细胞瘤的研究进展

多形性胶质母细胞瘤(glioblastoma mutiforme,GBM)是中枢神经系统中恶性程度最高的肿瘤,仅进行支持治疗,其平均生存期不足3个月.目前美国国家综合肿瘤网(National Comprehensive Cancer Network,NCCN)推荐的治疗方案是手术+放疗/替莫唑胺(Temozolomide,TMZ)同步化疗+替莫唑胺辅助化疗,根据2005年的一项III期试验,该方案可使患者的中位生存期达到14.6个月,2年生存率达到26%[1].尽管较历史对照有所提高,但总的疗效仍不满意,有必要寻找与传统途径不同机制的新治疗手段.目前研究主要集中在分子靶向治疗方面[2],研究较多的分子靶点包括血管内皮细胞生长因子(VEGF)、表皮生长因子(EGF)、血小板生长因子(PDGF)以及整合素(integrin)等.其中整合素抑制剂Cilengitide在基础及临床研究中获得了较满意的结果,是最有潜力的分子靶向药物之一.本文将对Cilengitide治疗GBM的研究进展做一总结.     

48例原发性胶质母细胞瘤的治疗经验

目的探讨胶质母细胞瘤手术加放疗、化疗综合治疗的疗效。方法 2007～2009年收治胶质母细胞瘤患者48例,均采用显微手术切除肿瘤;术后行全脑分割剂量放疗,部分患者采用立体定向放疗;同时联合化疗,方案是静脉滴注替尼泊甙60mg/(m2·d)+司莫司汀100mg/d,或口服替莫唑胺75mg(/m2·d)。结果肿瘤全切除43例,次全切除5例;术后无新增神经功能损伤33例,出现新的失语症状11例,新的肢体偏瘫症状10例。患者1年生存率为56.25%,肿瘤复发时间平均6.8个月。结论全切除肿瘤+术后早期行放疗+个性化化疗可延长胶质母细胞瘤患者生存期。     

精确放疗同步替莫唑胺治疗胶质母细胞瘤疗效初探

目的 探讨精确放疗同步替莫唑胺化疗对多形性胶质母细胞瘤的临床疗效.方法 回顾性分析2009年7月至2010年12月北京世纪坛医院收治的54例多形性胶质母细胞瘤,术后接受精确放疗(三维适形或调强放疗)同步替莫唑胺化疗,随后接受替莫唑胺辅助化疗.结果 全组共21例死亡,均死于肿瘤复发.全组1年总生存率为79.6％,1年无进展生存率为48.7％.32例出现复发,其中原位复发为16例.卡氏评分(KPS≥70分)组1年总生存率显著高于卡氏评分(KPS＜ 70分)组(86.8％与50.8％,P=0.005).全切或近全切除组1年总生存率高于部分切除组(84.4％与70.5％,P=0.067).仅2例出现3度以上不良反应(骨髓抑制).结论 精确放疗同步替莫唑胺化疗是多形性胶质母细胞瘤安全有效的治疗模式,卡氏评分和手术切除肿瘤的程度是影响生存的重要因素.     

BTPCs在胶质母细胞瘤治疗中的研究进展

胶质母细胞瘤(glioblastoma,GBM)是成人神经上皮性肿瘤中恶性程度最高、最具侵袭性、预后最差的肿瘤[1],中位生存期仅12~18.5个月[2]。脑胶质瘤的细胞来源仍众说纷纭,星形胶质细胞、神经干细胞和少突胶质前体细胞等均有可能是胶质瘤的起源细胞[3]。研究表明,高级别胶质瘤更有可能起源于神经干细胞(neural stem cell,NSCs)[4]。     

嵌合抗原受体T细胞治疗胶质母细胞瘤的研究进展

正胶质母细胞瘤(glioblastoma multiforme,GBM)是成人最常见的颅内原发性恶性肿瘤,中位生存期约15个月~([1])。目前,新诊断的GBM标准治疗包括最大化安全切除、替莫唑胺化疗联合同步放疗等~([2])。即使采用综合治疗,很短时间内仍不可避免地出现复发,预后不良。由于肿瘤的异质性、化疗耐药性、血脑屏障(blood-brain barrier,BBB)等因素,使得GBM的传统治疗面临巨大的挑战。     

Prospects of antibodies targeting CD47 or CD24 in the treatment of glioblastoma

Glioma is a malignant tumor with the highest incidence among all brain tumors (about 46% of intracranial tumors) and is the most common primary intracranial tumor. Among them, glioblastoma (GBM) is highly malignant and is one of the three refractory tumors with the highest mortality rate in the world. The survival time from glioblastoma diagnosis to death is only 14–16 months for patients with standard treatment such as surgery plus radiotherapy and chemotherapy. Due to its high malignancy and poor prognosis, in-depth studies have been conducted to explore effective therapeutic strategies for glioblastoma. In addition to the conventional surgery, radiotherapy, and chemotherapy, the glioblastoma treatments also include targeted therapy, immunotherapy, and electric field treatment. However, current treatment methods provide limited benefits because of the heterogeneity of glioblastoma and the complexity of the immune microenvironment within a tumor. Therefore, seeking an effective treatment plan is imperative. In particular, developing an active immunotherapy for glioblastoma has become an essential objective in the field. This article reviews the feasibility of CD47/CD24 antibody treatment, either individually or in combination, to target the tumor stem cells and the antitumor immunity in glioblastoma. The potential mechanisms underlying the antitumor effects of CD47/CD24 antibodies are also discussed.     

Taking advantage of neural development to treat glioblastoma

Glioblastoma (GBM) is by far the most common and most malignant primary adult brain tumor (World Health Organization grade IV), containing a fraction of stem‐like cells that are highly tumorigenic and multipotent. Recent research has revealed that GBM stem‐like cells play important roles in GBM pathogenesis. GBM is thought to arise from genetic anomalies in glial development. Over the past decade, a wide range of studies have shown that several signaling pathways involved in neural development, including basic helix–loop–helix, Wnt–β‐catenin, bone morphogenetic proteins–Smads, epidermal growth factor–epidermal growth factor receptor, and Notch, play important roles in GBM pathogenesis. In this review, we highlight the significance of these pathways in the context of developing treatments for GBM. Extrapolating knowledge and concepts from neural development will have significant implications for designing better strategies with which to treat GBM.     

胶质母细胞瘤肿瘤干细胞的分离培养与生物学特性研究

目的从人脑胶质母细胞瘤中分离培养脑肿瘤干细胞（brain tumorstem cells,BTSC）,并研究其生物学特性。方法利用无血清培养基和悬浮培养方法,从6例人胶质母细胞瘤标本中分离培养BTSC,并通过单克隆形成实验观察脑肿瘤干细胞球（brain tumor sphere,BTS）的形成过程。将BTSC接种于含血清培养基,观察其在体外的分化特点。将BTSC子代分化细胞更换培养条件,观察其在无血清培养基中的逆向分化现象。应用细胞免疫荧光染色对BTSC及其分化细胞进行鉴定。结果在人胶质母细胞瘤中成功分离出BTSC,其在无血清培养基中呈悬浮球状生长,具有很强的自我更新和增殖能力;免疫荧光显示其表达CD133。BTSC在含血清培养基中发生贴壁分化。分化后的子代细胞可表达CD133、神经元特异性烯醇化酶（NSE）和胶质纤维酸性蛋白（GFAP）。BTSC子代分化细胞在无血清条件下培养,能够再次增殖形成BTS,呈逆向分化现象。结论人胶质母细胞瘤中存在BTSC,其具有自我更新、无限增殖、多向分化以及逆向分化等生物学特性。     

Efficacy of concomitant and adjuvant temozolomide in glioblastoma treatment. A multicentre randomized study

Background and purposeThe common treatment in patients with newly diagnosed glioblastoma multiforme is the ultimately radical surgical removal of the tumour combined with radiotherapy. This study compared safety and efficacy of radiotherapy alone with radiotherapy combined with temozolomide (TMZ) given before, during, and after radiotherapy.Material and methodsThe patients operated on for glioblastoma multiforme during the first 21 postoperative days were randomly assigned to the group treated with radiotherapy alone (involved-field radiotherapy in 2 Gy fractions daily five times a week up to the total of 60 Gy over 6 weeks of treatment) or to the group treated with radiotherapy and TMZ, initially in the dose of 200 mg/m² during 5 postoperative days and after 23 days followed by 75 mg/m² of body surface area daily, 7 days a week (from the first to the last day of radiotherapy). On completion of radiotherapy, five complementary courses of TMZ were introduced (150–200 mg/m² for 5 days, repeated every 28 days). The primary outcome measure was overall survival.ResultsFifty-eight patients from 3 centres were included in the study. The mean age of patients was 55 years and all the patients underwent a surgical procedure of glioblastoma removal. The mean overall survival in the group treated with TMZ was 16.0 months, whereas in the group with radiotherapy alone the overall survival reached 12.5 months. 24-month survival reached 23% in patients treated with TMZ and 6.7% in those who received radiotherapy only. Haematological complications of third or fourth degree were present in 10% of patients treated with radiotherapy and TMZ.ConclusionsThe introduction of TMZ before, during and after radiotherapy for newly diagnosed glioblastoma multiforme gives clinically and statistically significant improvement of survival with unremarkably increased toxicity of the treatment.