Investigating tumour suppressor mutations in GBM which impact on tumour angiogenesis

研究 GBM 中肿瘤抑制突变对肿瘤血管生成的影响

• 批准号: 234086640
• 负责人: Professor Dr. Rainer Glass
• 金额: --
• 依托单位: Neurochirurgische Klinik und Poliklinik (Campus Großhadern)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/234086640?language=en
• 关键词: Investigating; tumour; suppressor; mutations; GBM

GBM are invasive and highly angiogenic tumours that origin from neoplastic neural precursor cells (NPCs). The vast majority of primary GBM is driven by genetic mutation in key tumour suppressor genes concomitant with accelerated activity of different proto‐oncogenes. With these key signal transduction pathways driving gliomagenesis separate tumour‐subtypes, which differ in prognosis and treatment characteristics, could be identified and are now termed proneural, classical or mesenchymal. Previously, we identified VEGF‐A as a tumour‐derived chemoattractant and proliferative factor for mouse and human NPCs. Our current preliminary results indicate that neoplastic transformation of (VEGFresponsive) NPCs converts these physiological stem cells into angiogenic (VEGF‐secreting) GBM cells.Our pilot studies suggest that consistent GBM‐subtype specific angiogenic patterns exist in mouse‐ and human‐GBM cells. In proneural GBM the p53‐status appears to be an important factor determining the expression levels of proangiogenic signalling molecules like VEGF‐A, while VEGF‐C/VEGFR3 signalling can constitute a therapeutic target for the remaining GBM‐subtypes. Consequently, we will investigate if distinct genetic markers in GBM have predictive power for individualised anti‐angiogenic treatment. Towards this end we have established subtype‐specific cell‐cultures from GBM‐biopsies and also from transgenic mice, orthotopic implantation models and transgenic mouse lines for the generation of GBM. Phenotypic and genetic analysis of these models will indicate the relation of GBM‐subtypes and p53‐status with the extent of GBM‐angiogenesis and with specific angiogenic signalling pathways. The therapeutic impact of VEGFR2 or VEGFR3‐blockade in different GBM subtypes will be explored in vitro and in vivo. After the clinical failure of anti‐angiogenic treatment using the VEGF‐A blocker bevacizumab it was suggested to restrict the application of the VEGF‐A blocker bevacizumab to patients suffering from proneural GBM. It will be interesting to determine if the p53‐status in proneural GBM provides a refined marker for patients potentially profiting from bevacizumab application. In addition our experiments are also suited to identify new therapeutic strategies for GBM‐patients suffering from the classical or mesenchymal GBM‐subtype.

GBM 是起源于肿瘤性神经前体细胞 (NPC) 的侵袭性和高度血管生成的肿瘤。绝大多数原发性 GBM 是由关键抑癌基因的基因突变以及不同原癌基因的活性加速引起的。通过这些驱动神经胶质瘤发生的关键信号转导途径，可以识别出预后和治疗特征不同的不同肿瘤亚型，现在被称为原神经型、经典型或间充质型。此前，我们确定 VEGF-A 是小鼠和人类 NPC 的肿瘤衍生趋化剂和增殖因子。我们目前的初步结果表明，（VEGF 响应性）NPC 的肿瘤转化将这些生理干细胞转化为血管生成（VEGF 分泌）GBM 细胞。我们的初步研究表明，小鼠和人类 GBM 细胞中存在一致的 GBM 亚型特异性血管生成模式。在原神经 GBM 中，p53 状态似乎是决定促血管生成信号分子（如 VEGF-A）表达水平的重要因素，而 VEGF-C/VEGFR3 信号传导可以构成其余 GBM 亚型的治疗靶点。因此，我们将研究 GBM 中的不同遗传标记是否对个体化抗血管生成治疗具有预测能力。为此，我们从 GBM 活检以及转基因小鼠、原位植入模型和用于生成 GBM 的转基因小鼠系中建立了亚型特异性细胞培养物。这些模型的表型和遗传分析将表明 GBM 亚型和 p53 状态与 GBM 血管生成程度和特定血管生成信号通路的关系。将在体外和体内探索 VEGFR2 或 VEGFR3 阻断对不同 GBM 亚型的治疗影响。在使用 VEGF-A 阻滞剂贝伐珠单抗进行抗血管生成治疗临床失败后，建议限制 VEGF-A 阻滞剂贝伐珠单抗在患有原神经性 GBM 的患者中的应用。确定原神经性 GBM 中的 p53 状态是否为可能从贝伐单抗应用中获益的患者提供了一个精细的标记，这将是一件很有趣的事情。此外，我们的实验还适合为患有经典或间充质 GBM 亚型的 GBM 患者确定新的治疗策略。