Investigating the role of epigenetic remodelling in glioblastoma in response to therapy

研究表观遗传重塑在胶质母细胞瘤中对治疗的反应的作用

• 批准号: MR/T020504/1
• 负责人: Lucy Stead
• 金额: $ 201.35万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT020504%2F1
• 关键词: Investigating; role; epigenetic; remodelling; glioblastoma

Glioblastoma (GBM) is the most common and most deadly form of brain cancer. GBM tumours are solid but many of the cancer cells break away and invade the surrounding normal brain tissue, making complete surgical removal impossible. After surgery, patients commonly receive radio- and chemo-therapy but GBM tumours typically grow back within 6 to 9 months and are fatal. This is why brain tumours kill more people aged under 40 than any other cancer. New drugs that were developed to target the DNA mutations that are commonly found in GBM tumours have failed to increase patient survival. It is now thought that this is because, although such mutations may have caused the tumour to form, they are not responsible for its continued growth and ability to resist treatment. To specifically identify what properties of GBM cancer cells do enable them to resist treatment, I have collected, characterised and compared paired GBM tumours from multiple patients i.e. the first tumour that was diagnosed and removed and the post-treatment recurrent tumour from cases where the latter also underwent surgery. I have found that a specific set of genes are universally altered in GBM by treatment, but whether they become more switched on or more switched off after therapy is patient dependent and enables them to be split into two classes. I will determine whether assignment to one class versus another alters the likely survival for GBM patients or can be used to better predict the likely benefit of treatment with one type of therapy versus another. Furthermore, if the changes that I have observed in the specific genes are actually required by the GBM cells in order for them to survive treatment, then developing drugs to inhibit the changes may provide a more effective treatment for GBM. I plan to use my fellowship to test just that. I will use both computational analysis of patient datasets to reveal the biology underpinning the observed gene changes and further profiling of GBM tumour pairs to confirm whether the changes are driven by a single master regulator protein. I will then grow GBM tumours in the laboratory and use experimental approaches to stop them being able to undergo the observed changes, before administering the same radio- and chemo-therapy that patients receive to see if more cells die versus tumours where the changes are allowed to take place. Finally, I will determine whether drugs can be adapted or developed that restrict the gene changes in patients, making their GBM tumours more susceptible to killing as part of more effective treatment strategies.

胶质母细胞瘤(GBM)是最常见和最致命的脑癌形式。基底膜肿瘤是坚固的，但许多癌细胞脱离并侵入周围的正常脑组织，使得完全手术切除是不可能的。手术后，患者通常接受放射和化疗，但GBM肿瘤通常在6至9个月内复发，并具有致命性。这就是为什么40岁以下的人死于脑瘤的人数比死于其他任何癌症的人都多。针对GBM肿瘤中常见的DNA突变而开发的新药未能提高患者的存活率。现在认为这是因为，尽管这些突变可能导致了肿瘤的形成，但它们并不是导致肿瘤持续生长和抵抗治疗的原因。为了具体确定GBM癌细胞的哪些特性确实使它们能够抵抗治疗，我收集了来自多个患者的成对的GBM肿瘤，即第一个被诊断并切除的肿瘤，以及治疗后复发的肿瘤，后者也接受了手术。我发现，在GBM中，一组特定的基因在治疗过程中普遍会发生变化，但治疗后这些基因是变得更加开启还是更加关闭取决于患者，并使它们能够分为两类。我将确定一个类别与另一个类别的分配是否会改变GBM患者的可能生存，或者是否可以用来更好地预测一种治疗类型与另一种治疗类型的治疗可能带来的好处。此外，如果我在特定基因中观察到的变化实际上是GBM细胞为了让它们在治疗中存活所必需的，那么开发抑制这些变化的药物可能会为GBM提供更有效的治疗。我计划利用我的奖学金来检验这一点。我将使用对患者数据集的计算分析来揭示支持观察到的基因变化的生物学，并进一步分析GBM肿瘤对，以确认这些变化是否由单一的主调节蛋白驱动。然后，我将在实验室培养GBM肿瘤，并使用实验方法阻止它们能够经历观察到的变化，然后进行与患者相同的放化疗，看看是否有更多的细胞死亡，而不是允许发生变化的肿瘤。最后，我将确定是否可以调整或开发限制患者基因变化的药物，使他们的GBM肿瘤更容易被杀死，作为更有效的治疗策略的一部分。

项目成果

Benchmarking pipelines for subclonal deconvolution of bulk tumour sequencing data.

• DOI: 10.1038/s41467-021-26698-7
• 发表时间: 2021-11-04
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Tanner G;Westhead DR;Droop A;Stead LF
• 通讯作者: Stead LF

Longitudinal analysis of diffuse glioma reveals cell state dynamics at recurrence associated with changes in genetics and the microenvironment

弥漫性胶质瘤的纵向分析揭示了与遗传学和微环境变化相关的复发时的细胞状态动态

• DOI: 10.1101/2021.05.03.442486
• 发表时间: 2021
• 作者: Varn F

The epigenetic evolution of gliomas is determined by their IDH1 mutation status and treatment regimen

• DOI: 10.1101/2021.08.09.455687
• 发表时间: 2021-08
• 期刊: bioRxiv
• 作者: T. Malta;Thais S Sabedot;I. Datta;L. Garofano;W. Vallentgoed;F. Varn;Kenneth Aldape;F. D’Angelo

Treating glioblastoma often makes a MES

治疗胶质母细胞瘤通常会导致 MES

• DOI: 10.1038/s43018-022-00471-1
• 发表时间: 2022
• 期刊: Nature Cancer
• 影响因子: 22.7
• 作者: Stead L

GBMdeconvoluteR accurately infers proportions of neoplastic and immune cell populations from bulk glioblastoma transcriptomics data.

• DOI: 10.1093/neuonc/noad021
• 发表时间: 2023-07-06
• 期刊: Neuro-oncology
• 影响因子: 15.9
• 作者: Ajaib S;Lodha D;Pollock S;Hemmings G;Finetti MA;Gusnanto A;Chakrabarty A;Ismail A;Wilson E;Varn FS;Hunter B;Filby A;Brockman AA;McDonald D;Verhaak RGW;Ihrie RA;Stead LF
• 通讯作者: Stead LF