Oncolytic adenoviruses for treatment of brain tumours

Standard therapies are not capable of curing patients with malignant glioma; more than 90% of patients die within 2 years after diagnosis. Gene therapy appeared as a promising new approach for this disease. However, results of clinical trials with replication deficient viral vectors were disappointing. The main reasons being poor transduction efficiency of adenovirus towards glioma cells and limited spread and distribution of the vector in the tumour. With the increasing knowledge of viral genetics and its functions, an attractive alternative tool to kill malignant glioma cells has been developed: Replicating adenovirus as an oncolytic agent. This type of therapy, also referred to as virotherapy, has the potential to overcome some of the limitations connected with replication deficient adenoviral vectors. In this review the authors describe the latest developments in strategies that are being used to create a tumour- or glioma- selective replicating adenovirus. Special attention is given to the methods of viral delivery to an infiltrating tumour in the brain, regarding optimal dose and toxicity. Furthermore, the role of conventional antitumour treatments, such as irradiation and chemotherapy, in enhancing the effect of virotherapy is being emphasised.     

Antiangiogenic blockage: a new treatment for glioblastoma

Background: Angiogenesis is common in cancer and reflects the requirement for a vascular network to support continued uncontrolled growth. Two strategies of antiangiogenic therapy have emerged; one targeting VEGF (growth-factor-ligand-based antagonists) and the second targeting VEGF receptor (receptor-based antagonists, small-molecule tyrosine kinase inhibitors). Methods: The literature as reviewed by Reardon et al. regarding treatment of recurrent high-grade gliomas (HGG) with antiangiogenic therapy (predominantly ligand-based and administered in conjunction with cytotoxic chemotherapy) reports response rates of 30 – 60% and 6-month progression-free survival of 25 – 50%. Problems include new antiangiogenic-class side effects and control of administration and timing in relation to surgery. Results/conclusions: Ligand-based antiangiogenic therapy is a compelling targeted therapy for HGG and will continue to emerge as an important antiglioma therapy. Further studies are required to define the population of patients in whom this therapy is of benefit, identify the optimal dose and schedule, characterize the value of co-administered (cytotoxic and targeted) therapies and establish validated response measures.     

Nicotine does not affect stem cell properties requisite for suicide gene therapy against glioma

ABSTRACT

Objective: 

Glioblastoma is one of the most lethal tumors in adult central nervous system with a median survival of a year and half and effective therapeutic strategy is urgently needed. For that reason, stem cell-based suicide gene therapies have attracted much interest because of potent tumor tropism of stem cells and bystander effect. In this current clinical situation, stem cells are promising delivery tool of suicide genes for glioma therapy. Since habitual cigarette smoking still prevails worldwide, we investigated the effect of nicotine on stem cell tropism toward glioma and gap junctional intercellular communication (GJIC) function between glioma and stem cells, both of which are important for suicide gene therapies. Methods: Mouse induced pluripotent stem cell-derived neural stem cells (iPS-NSCs) and human dental pulp mesenchymal stem cells (DPSCs) were used. The effect of nicotine on tumor tropism to glioma-conditioned medium (CM) at a non-cytotoxic concentration was assessed with Matrigel invasion assay. Nicotine effect on GJIC was assessed with the scrape loading/dye transfer (SL/DT) assay for co-culture of glioma and stem cells and the parachute assay among glioma cells using high-content analysis. Results: Tumor tropism of iPS-NSCs toward GL261-CM and DPSCs toward U251-CM was not affected by nicotine (0.1 and 1 µM). Nicotine at the concentrations equivalent to habitual smoking (1 µM) did not affect GJIC of iPS-NSC/GL261 and DPSC/U251 and GJIC among each glioma cells. Conclusions: The study demonstrated that non-cytotoxic concentrations of nicotine did not significantly change the stem cell properties requisite for stem cell-based suicide gene therapy.     

A druggable addiction to de novo pyrimidine biosynthesis in diffuse midline glioma

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Monitoring of gliomas in vivo by diffusion MRI and 1H MRS during gene therapy‐induced apoptosis: interrelationships between water diffusion and mobile lipids

The measurement of water diffusion by diffusion‐weighted MRI (DWI) in vivo offers a non‐invasive method for assessing tissue responses to anti‐cancer therapies. The pathway of cell death after anti‐cancer treatment is often apoptosis, which leads to accumulation of mobile lipids detectable by ¹H MRS in vivo. However, it is not known how these discrete MR markers of cell death relate to each other. In a rodent tumour model [i.e. ganciclovir‐treated herpes simplex thymidine kinase (HSV‐tk) gene‐transfected BT4C gliomas], we studied the interrelationships between water diffusion (Trace{D}) and mobile lipids during apoptosis. Water diffusion and water‐referenced concentrations of mobile lipids showed clearly increasing and interconnected trends during treatment. Of the accumulating ¹H MRS‐visible lipids, the fatty acid ? CH ?CH ? groups and cholesterol compounds showed the strongest associations with water diffusion (r² = 0.30; P < 0.05 and r² = 0.48; P < 0.01, respectively). These results indicate that the tumour histopathology and apoptotic processes during tumour shrinkage can be interrelated in vivo by DWI of tissue water and ¹H MRS of mobile lipids, respectively. However, there is considerable individual variation in the associations, particularly at the end of the treatment period, and in the relative compositions of the accumulating NMR‐visible lipids. The findings suggest that the assessment of individual treatment response in vivo may benefit from combining DWI and ¹H MRS. Absolute and relative changes in mobile lipids may indicate initiation of tumour shrinkage even when changes in tissue water diffusion are still small. Conversely, greatly increased water diffusion probably indicates that substantial cell decomposition has taken place in the tumour tissue when the ¹H MRS resonances of mobile lipids alone can no longer give a reliable estimate of tissue conditions. Copyright © 2008 John Wiley & Sons, Ltd.     

The additive effect ofα-difluoromethylornithine (DFMO) and radiation therapy on a rat glioma model

Summary The effects of -difluoromethylornithine (DFMO), radiation and the therapy of their combination were investigated in rats bearing G-XII glioma. DFMO treatment as well as radiation therapy prolonged the survival period when compared to the results in non-treated control rats. The combination therapy showed a greater effect on the survival rate than the single therapies, the effect being additive. The concentration of putrescine, spermidine, andN ¹-acetylspermidine in tumor tissues was lowered by DFMO, while that of spermine was slightly elevated. Radiation decreased the concentration of all the polyamines, putrescine, spermidine, spermine andN ¹-acetylspermidine. The concomitant treatment with DFMO and radiation further decreased the concentrations of putrescine andN ¹-acetylspermidine in tumor tissues. The survival period of glioma-bearing rats is inversely correlated with the tissue levels of putrescine plusN ¹-acetylspermidine.Abbreviations DFMO -difluoromethylornithine - BrdUrd bromodeoxyuridine     

A-kinase interacting protein 1 is sufficiently expressed and positively associates with WHO grade,meanwhile predicts unfavorable overall survival independently in glioma patients

The present study aimed to investigate the association of A-kinase interacting protein 1 (AKIP1) with clinical characteristics, and further explore the prognostic value of AKIP1 in glioma patients.Totally 168 glioma patients who underwent tumor resection were analyzed, and their tumor tissue specimens were acquired for the detection of AKIP1 expression by immunohistochemistry (IHC), which was scored by a semi-quantitative method considering staining intensity and staining density.According to AKIP1 expression in tumor tissues of glioma patients, there were 65 (38.7%) patients with AKIP1 low expression (IHC score 0–3), 48 (28.6%) patients with AKIP1 high + expression (IHC score 4–6), 42 (25.0%) patients with AKIP1 high++ expression (IHC score 7–9) and 13 (7.7%) patients with AKIP1 high+++ expression (IHC score 10–12), respectively. AKIP1 expression was positively associated with World Health Organization grade. Overall survival (OS) was the lowest in the patients with AKIP1 high+++ expression, followed by those with AKIP1 high++ expression and those with AKIP1 high+ expression, and highest in those with AKIP1 low expression. Further subgroup analysis exhibited that AKIP1 expression was negatively associated with OS especially in high-grade glioma patients. In addition, AKIP1 expression was negatively associated with OS in all subgroups of patients with/without adjuvant radiotherapy, with/without adjuvant chemotherapy. Further multivariate Cox''s regression exhibited that AKIP1 high expression was an independent predictive factor for worse OS.AKIP1 presents with the potential to be a novel biomarker for tumor management and prognosis surveillance in glioma patients.     

SYT16 is a prognostic biomarker and correlated with immune infiltrates in glioma: A study based on TCGA data

BackgroundGlioma is the most lethal primary brain tumor. Lower-grade glioma (LGG) is the crucial pathological type of Glioma. Immune-infiltration of the tumor microenvironment positively associated with overall survival in LGG. SYT16 is a gene has not been reported in cancer. We assess the role of SYT16 in LGG, via the publicly available TCGA database.MethodsGene Expression Profiling Interactive Analysis (GEPIA) was used to analyze the expression of SYT16 in LGG. We evaluated the influence of SYT16 on survival of LGG patients by survival module. Then, datasets of LGG were downloaded from TCGA. The correlations between the clinical information and SYT16 expression were analyzed using logistic regression. Univariable survival and Multivariate Cox analysis was used to compare several clinical characteristics with survival. we also explore the correlation between SYT16 and cancer immune infiltrates using CIBERSORT and correlation module of GEPIA. Gene set enrichment analysis (GSEA) was performed using the TCGA dataset. In addition, we use TIMER to explore the collection of SYT16 Expression and Immune Infiltration Level in LGG and to explore cumulative survival in LGG.ResultsThe univariate analysis using logistic regression, indicated that increased SYT16 expression significantly correlated with the tumor grade. Moreover, multivariate analysis revealed that the up-regulated SYT16 expression is an independent prognostic factor for good prognosis. Specifically, SYT16 expression level has significant negative correlations with infiltrating levels of B cell, CD4+ T cells, Macrophages, Neutrophils and DCs in LGG. In addition, GSEA identified ingle organism behavior, gated channel activity, cognition, transporter complex and ligand gated channel activity  in Gene Ontology (GO) were differentially enriched in the high SYT16 expression phenotype pathway. Neuroactive ligand receptor interaction, calcium signaling pathway, long term potentiation, type II diabetes mellitus and long term depression were identified as differentially enriched  pathway in Kyoto Encyclopedia of Genes and Genomes (KEGG).ConclusionSYT16 is a Prognostic Biomarker and Correlated with Immune Infiltrates in LGG.     

诊疗一体化胶质瘤靶向纳米粒增效声动力治疗及多模态显像：体外实验研究

目的 制备胶质瘤靶向诊疗一体化纳米粒,观察体外多模态显像及对U87细胞主动靶向能力和增效声动力治疗（SDT）效果。方法 以双乳化法制备载IR780和全氟戊烷（PFP）纳米粒（IR780-PFP@PLGA）,验证其体外光声（PA）/超声（US）/荧光（FL）多模态显像能力;以细胞计数试剂盒（CCK-8）检测细胞毒性,激光共聚焦显微镜观察其主动靶向能力,通过单线氧荧光探针（SOSG）检测法、JC-1染色法、2'',7''-二氯荧光黄双乙酸盐（DCFH-DA）染色法、钙黄绿素/碘化丙啶（Calcein-AM/PI）双染及CCK-8评价其增效SDT效果。结果 所制备IR780-PFP@PLGA呈圆形,形态规则,粒径均匀,平均（240.67±1.30） nm,表面电位（-9.50±0.06） mV,IR780包封率（92.03±0.42）%;经激光辐照后其PA和FL信号强度呈浓度依赖性,经低强度聚焦超声（LIFU）辐照后表现出良好US对比度成像能力和较强U87细胞靶向能力,并呈活性氧（ROS）浓度依赖。于U87细胞中检出大量ROS,线粒体膜电位明显降低,细胞毒作用明显。结论 成功构建的IR780-PFP@PLGA不仅可用于PA/US/FL多模态显像并具有良好体外寻靶能力,还可通过声致相变（ADV）增强SDT疗效,有望用于多模态成像指导下早期诊断和靶向精准治疗脑胶质瘤并评估疗效。