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

胶质母细胞瘤（GBM）是最常见和最致命的脑癌。GBM肿瘤是实体的，但许多癌细胞会脱落并侵入周围的正常脑组织，因此不可能通过手术完全切除。手术后，患者通常接受放疗和化疗，但GBM肿瘤通常在6至9个月内重新生长，并且是致命的。这就是为什么40岁以下死于脑肿瘤的人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生存率。现在人们认为，这是因为，尽管这些突变可能导致了肿瘤的形成，但它们并不负责肿瘤的持续生长和抵抗治疗的能力。为了明确确定GBM癌细胞的哪些特性使它们能够抵抗治疗，我收集、描述并比较了来自多个患者的成对GBM肿瘤，即第一个被诊断并切除的肿瘤和治疗后复发的肿瘤，后者也接受了手术。我发现，在GBM中，一组特定的基因在治疗后普遍发生了改变，但它们在治疗后是更加开启还是更加关闭，这取决于患者，并使它们被分为两类。我将确定是否分配到一个类别与另一个类别会改变GBM患者的可能生存，或者可以用来更好地预测一种治疗与另一种治疗的可能益处。此外，如果我在特定基因中观察到的变化实际上是GBM细胞在治疗中生存所必需的，那么开发药物来抑制这些变化可能会为GBM提供更有效的治疗方法。我打算用我的奖学金来验证这一点。我将使用患者数据集的计算分析来揭示所观察到的基因变化的生物学基础，并进一步分析GBM肿瘤对，以确认这些变化是否由单个主调节蛋白驱动。然后，我将在实验室培养GBM肿瘤，并使用实验方法阻止它们发生观察到的变化，然后再进行与患者接受的相同的放疗和化疗，以观察是否有更多的细胞死亡，而肿瘤则允许发生变化。最后，我将确定是否可以调整或开发药物来限制患者的基因变化，使他们的GBM肿瘤更容易被杀死，作为更有效治疗策略的一部分。

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.