Targeting metabolic vulnerabilities in glioblastoma

胶质母细胞瘤(GBM)是所有癌症中最致命的癌症之一。因此，新的治疗策略迫不及待地 需要的。我们和其他人已经证明，代谢重新编程是GBM的一个关键特征，以适应 更高的能量、营养和氧化还原需求，以支持肿瘤的生长和存活。最突出的 这种代谢重新编程的特点是向高糖代谢转变。最近的证据 提示在GBM中，致癌信号调节葡萄糖的利用。相应地，抑制致癌作用 信号可以扰乱葡萄糖代谢，导致细胞能量和代谢中间产物减少 合成代谢过程。然而，靶向癌基因调节的糖代谢的治疗潜力 GBM仍然是个谜。我们提出了令人信服的初步数据，表明急性抑制EGFR- GBM中最常见的癌基因改变-可以迅速而有效地减弱葡萄糖的摄取和 因此，患者衍生的GBM模型中的葡萄糖代谢。由于这种“改变”的代谢状态， GBM模型显示内源性细胞凋亡与药理学P53激活具有协同作用。我们还证明了 18F-脱氧葡萄糖(FDG)和正电子发射断层扫描(PET)可用作快速(几小时内)， 非侵入性生物标志物，可预测对这种新的合理组合的敏感性。在本修订版R01中 应用，我们扩展了这些令人兴奋的初步研究，并在目标1中研究了精确的信号和 EGFR抑制使基底膜对P53活化敏感的代谢机制。在目标2中，使用已建立的 BH3图谱技术，我们建议表征导致P53- 抑制EGFR调节的葡萄糖代谢后的依赖致死性。最后，在目标3中，我们将 确定联合靶向癌基因调节的葡萄糖代谢(例如，与EGFRi)和 药理学P53激活(与罗氏联合)对直接来自患者的原位GBM有效 异种移植物。我们还将评估18FDG PET是否可以作为一种强有力的非侵入性生物标志物 通过一项分子富集型的先导性临床试验，用EGFRi对葡萄糖代谢的快速变化进行量化 复发的基底膜患者。本申请中提出的研究提出了一种新的组合策略， 一种非侵入性的预测生物标记物，旨在对新陈代谢和细胞凋亡途径进行特定操作 在恶性胶质瘤中，并有可能改变目前胶质瘤治疗的方法。

Glioblastoma (GBM) is one of the most lethal of all cancers. As such, new therapeutic strategies are desperately needed. We and others have shown that metabolic reprogramming is a key feature of GBM to accommodate the heightened energetic, nutrient and redox requirements to support tumor growth and survival. The most prominent characteristics of this metabolic reprogramming are a shift to high glucose metabolism. Recent evidence suggests that oncogenic signaling regulates glucose utilization in GBM. Accordingly, inhibition of oncogenic signaling can disrupt glucose metabolism, leading to reduced metabolic intermediates for cellular energetic and anabolic processes. However, the therapeutic potential of targeting oncogene-regulated glucose metabolism in GBM remains enigmatic. We present compelling preliminary data demonstrating that acute inhibition of EGFR – the most frequently altered oncogene in GBM - can rapidly and potently attenuate glucose uptake and consequently glucose metabolism in patient-derived GBM models. As a result of this “altered” metabolic state, GBM models show synergistic intrinsic apoptosis to pharmacological p53 activation. We also demonstrate that 18F-flurodeoxyglucose (FDG) and positron emission tomography (PET) can be used as a rapid (within hours), non-invasive biomarker that may predict sensitivity to this new rational combination. In this revised R01 application, we extend on these exciting preliminary studies and investigate in Aim 1 the precise signaling and metabolic mechanisms whereby EGFR inhibition sensitizes GBMs to p53 activation. In Aim 2, using established BH3 profiling technology, we propose to characterize the pro- and anti-apoptotic signatures resulting in p53- dependent lethality following inhibition of EGFR-regulated glucose metabolism. Finally, in Aim 3 we will determine whether combined targeting of oncogene-regulated glucose metabolism (e.g., with EGFRi) and pharmacological p53 activation (in collaboration with Roche) is efficacious in direct-from-patient orthotopic GBM xenografts. We will also evaluate whether 18FDG PET can serve as a robust non-invasive biomarker for quantifying rapid changes in glucose metabolism with EGFRi via a pilot clinical trial in molecularly enriched recurrent GBM patients. The studies proposed in this application present a new combination strategy, coupled with a non-invasive predictive biomarker, aimed for specific manipulation of metabolism and apoptotic pathways in malignant glioma and have the long term potential to shift current approaches in glioma therapy.