Targeting T Cells with Bispecific Antibodies for Cancer Therapy

Bispecific antibodies (BiAbs) offer a unique opportunity to redirect immune effector cells to kill cancer cells. BiAbs combine the benefits of different binding specificities of two monoclonal antibodies (mAbs) into a single construct. This unique feature of BiAbs enables approaches that are not possible with single mAbs. Advances in antibody engineering and antigen profiling of malignant cells have led to the development of a number of BiAb formats and their combinations for redirecting effector cells to tumor targets. There have been significant advances in the design and application of BiAbs for intravenous and local injection.The initial barrier of cytokine storm has been partially overcome by more recent constructs that have improved clinical effectiveness without dose-limiting toxicities. Since the recent revival of BiAbs, there has been multiple, ongoing, phase I/II and III trials, and some promising clinical outcomes have been reported in completed clinical studies. This review focuses on arming T cells with BiAbs to create the 'poor man's cytotoxic lymphocyte'.     

靶向HSF1在肿瘤治疗中的作用

目前许多热休克蛋白90抑制剂已经用于抗癌的临床试验,这些抑制剂的产生是肿瘤治疗的里程碑,为癌症治疗探索出更多的新方法。高度保守的热休克转录因子1(heat shock factor 1, HSF1)作为转录因子促进热休克蛋白基因的转录和表达,肿瘤细胞比正常细胞更依赖其功能, HSF1对肿瘤的起始和维持是必需的：调控肿瘤细胞异常信号,抑制有丝分裂增加基因组非整倍性,抑制肿瘤细胞发生凋亡和促进肿瘤细胞转移和代谢等。随着很多小分子药物筛选方法不断的发现和运用,目前已有部分以HSF1为靶点的化合物研究报道,主要有槲皮素和雷公藤内酯抑制HSF1,同时减少热休克反应。文章综述了以HSF1为靶点的药物的研究前沿,并分别阐述了这类药物作用特点和机制。     

HER2分子与肿瘤靶向治疗

HER2分子是表皮生长因子受体家族的第二位成员,对细胞的生长、分化及存活有着重要的调节作用,在乳腺癌、卵巢癌、肺腺癌、肾细胞癌中其过表达与否是患者预后的重要指标。研究表明它与表皮生长因子受体家族其他3位成员形成异二聚体,通过多种信号转导途径促进肿瘤的增殖、转移、耐药性的产生,是肿瘤基因治疗的重要靶位点。     

图像引导HIFU治疗靶区精确定位

靶区精确定位是B超引导HIFU治疗的一个难题。本文利用患者术前采集的CT／MR图像序列与实时B超共同引导进行HIFU治疗靶区精确定位,在没有集成MR设备的HIFU治疗机器上利用了CT／MR图像靶区定位精确的优点。首先在CT／MR图像上进行靶区分割与三维表面重建,再利用三视图多模态医学图像配准技术,将重建的靶区信息映射到超声图像,实现了超声图像上靶区的精确定位。整个引导过程主要包括图像采集、预处理、分割、靶区重建以及多模态图像配准几个部分。这种融合CT／MR图像信息的定位技术有望更好地解决B超引导HIFU治疗中的靶区定位难题。     

Anticancer Therapy Targeting Telomeres and Telomerase

Normal human somatic cells undergo telomeric attrition causing replicative senescence. Most immortal cancer cells cope with this by upregulating the active form of telomerase. Long-term inhibition of telomerase results in telomeric attrition and highly specific killing of cancer cells, in which the maintenance of telomere length is reliant on telomerase activity. Unfortunately, telomere erosion requires many cell divisions, possibly opening the way for acquired drug resistance. Recent attempts to solve this problem include the development of drugs that are more potent catalytic inhibitors, deny telomerase access to the telomere in situ, or affect telomere structure; some of these drugs have entered clinical trials. Combinations of these approaches may ultimately produce the best clinical results. This article reviews the latest results in both basic and applied telomere research that indicate the most promising avenues for future anticancer drug development in this area.     

Current Status and Challenges Associated with Targeting mTOR for Cancer Therapy

The phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in the regulation of cellular growth, survival, and proliferation. Inappropriate activation of PI3K/Akt/mTOR signaling can promote a cellular environment that is favorable for transformation. In fact, dysregulation of this pathway, as a result of genetic mutations and amplifications, is implicated in a variety of human cancers. Therefore, mTOR has emerged as a key target for the treatment of cancer, particularly in the treatment of tumors that exhibit increased mTOR signaling as a result of genetic lesions. The immunosuppressant sirolimus (rapamycin) directly inhibits mTOR activity and suppresses the growth of cancer cells in vitro and in vivo. As a result, a number of sirolimus derivatives have been developed as anti-cancer therapies, and these compounds are currently under investigation in phase I–III clinical trials. In this review, we summarize the use of sirolimus derivatives in clinical trials and address some of the challenges associated with targeting mTOR for the treatment of human cancer.     

Targeting Cancer Stem Cells in Cancer Prevention and Therapy

The cancer stem cell hypothesis is an attractive framework within which one may think about cancer initiation, recurrence, and metastasis, and methods to devise treatment strategies for cancers. Although all cancers do not appear to sustain themselves with cancer stem cells, but also through a dominant cell population, creating strategies for cancer treatment which include cancer stem cells as targets seems reasonable. In this perspective we discuss possible strategies for controlling the viability and tumorigenecity of cancer stem cells, and extend our discussion to strategies approaching the prevention of cancer.     

Biodegradable Microparticles for in vivo Glomerular Targeting: Implications for Gene Therapy of Glomerular Disease

Glomerular disease is the most common cause of kidney failure in the United States. Gene therapy represents a novel approach to the treatment of diseases of the glomerulus, but necessitates safe and accurate tissue targeting, combined with efficient gene transfer into the cells of interest. Our previous work demonstrated effective glomerular gene transfer after arterial injection of replication deficient recombinant adenovirus complexed to 16 m polystyrene microspheres. The insoluble nature of polystyrene makes glomerular ischemia a potential complication of the procedure. On this basis, we postulated that biodegradable gelatin particles could serve as transport vehicles in this system. To address this question, we assessed the in vivo degradation of Tc-99m labeled gelatin or polystyrene particles in the kidney following selective renal artery injection. Radioactivity declined 2–3 fold faster in a gelatin-injected pig kidney, when compared to polystyrene injected animals. The discrepancy in signal loss between gelatin and polystyrene injected animals could not be explained by differences in the rate of dissociation of Tc-99m from each particle type, and suggest that gelatin particles degrade once lodged in the glomerular capillary. These data suggest that biodegradable gelatin particles may help to minimize ischemic potential when used to shuttle therapeutic DNA to the glomerulus.     

纳米铁核素靶向治疗肿瘤的辐射效应研究

目的:综合考察纳米铁核素(59Fe)的照射剂量率和照射时间对杀死肿瘤细胞的影响,为低剂量率的β粒子放射性核素靶向疗法提供指导。方法:采用的三个肿瘤细胞系为:SKBR-3乳腺癌、U-118MG神经胶质瘤和A-431宫颈癌;实验模型为:在每一个样品中取103个肿瘤细胞,用低剂量率的β粒子照射;初始剂量率为:0.1 Gy/h～0.8 Gy/h;持续照射时间为:1天、3天或者7天。结果:分别用0.2 Gy/h～0.3 Gy/h和0.4 Gy/h～0.6 Gy/h的剂量率连续照射肿瘤细胞7天和3天,能够将所有肿瘤细胞样品中的细胞杀死。细胞的总辐射剂量为30 Gy～40 Gy。而用0.8 Gy/h的剂量率照射24小时后,仅SKBR-3细胞被杀死,其它肿瘤细胞系的所有细胞都能自动修复。结论:在低剂量率的β粒子放射性核素靶向疗法中,该实验结果为照射剂量率和照射时间的确定提供了指导。     

恶性肿瘤治疗药物相关个体化检测研究进展

恶性肿瘤靶向治疗药物和化疗药物通过作用于信号传导通路中的特定基因位点而发挥药效,通路中基因的突变和表达状态与药效及毒副作用密切相关,通过对相关基因检测来制定个性化的治疗方案,能显著提高治疗的有效率,减少药物毒副作用.本文就常用靶向治疗药物和化疗药物的基因检测,从相关靶标、临床意义、检测方法、标本采集、核酸提取、质量控制及注意事项等方面进行了总结,以期为恶性肿瘤的临床治疗提供可靠的个体化用药参考.