Project 2: Targeting metabolic vulnerabilities in glioblastoma

项目2：针对胶质母细胞瘤的代谢易损性 摘要/摘要 胶质母细胞瘤(GBM)是所有癌症中最致命的癌症之一。因此，新的治疗策略是 迫切需要。我们和其他人已经证明，新陈代谢重新编程是GBM的一个关键特征 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。 这种代谢重新编程的最显著特征是向高糖酵解通量转变。近期 有证据表明，致癌信号调节GBM中的糖酵解通量。因此，抑制 致癌信号可以破坏糖酵解，导致细胞能量代谢中间产物减少 和合成代谢过程。然而，靶向癌基因调控的糖酵解在GBM中的治疗潜力 仍然是个谜。我们提供了令人信服的初步数据，表明急性抑制EGFR-the 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， 因此，基底膜中的糖酵解通量。由于这种“改变”的新陈代谢状态，GBM模型显示 对药理学P53激活的协同致死性。我们还证明了18F-氟代脱氧葡萄糖(FDG) 正电子发射断层扫描(PET)可以作为一种快速(几小时内)、非侵入性的生物标志物， 可能预示着对这种新的组合方法的敏感性。在这项提案中，我们扩展了这些令人兴奋的 初步调查结果。在目标1中，我们将研究联合靶向EGFR调节的糖酵解 (如脉冲式Erlotinib)和P53激活(如Idasanutlin)在直接从患者开始的原位移植中是有效的 GBM异种移植。我们还将确定18F-FDG PET是否可以作为一种强有力的预测生物标志物 对这种药物组合的敏感性。在目标2中，我们建议询问 在药物糖酵解减弱下，P53在诱导细胞凋亡中的意外作用。最后，在目标3中， 我们提出了一项临床试验，以测试EGFR抑制与一种新的P53激活剂(Idasanutlin， (由罗氏提供)对复发的基底膜患者安全有效。纳入这项试验的是 评价18F-FDGPET作为这种新的靶向治疗方法的无创性和早期预测疗效的价值 GBM代谢。本申请中提出的研究提出了一种新的组合策略，通过 恶性脑胶质瘤代谢和凋亡通路的特异性调控及长期作用 改变目前脑胶质瘤治疗方法的可能性。

Project 2: Targeting metabolic vulnerabilities in glioblastoma SUMMARY/ABSTRACT 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 glycolytic flux. Recent evidence suggests that oncogenic signaling regulates glycolytic flux in GBM. Accordingly, inhibition of oncogenic signaling can disrupt glycolysis, leading to reduced metabolic intermediates for cellular energetic and anabolic processes. However, the therapeutic potential of targeting oncogene-regulated glycolysis 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, glycolytic flux in GBM. As a result of this “altered” metabolic state, GBM models show synergistic lethality 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 combination approach. In this proposal, we expand on these exciting preliminary findings. In Aim 1, we will investigate whether combined targeting of EGFR-regulated glycolysis (e.g., pulsatile Erlotinib) and p53 activation (e.g., Idasanutlin) is efficacious in straight-from-patient orthotopic GBM xenografts. We will also determine whether 18F-FDG PET can serve as a robust predictive biomarker for sensitivity to this drug combination. In Aim 2, we propose to interrogate the underlying mechanism of the unexpected role of p53 in eliciting apoptosis under pharmacological glycolytic attenuation. Finally, in Aim 3, we propose a clinical trial to test whether EGFR inhibition combined with a novel p53 activator (Idasanutlin, provided by Roche) is safe and efficacious in recurrent GBM patients. Incorporated into this trial is the evaluation of 18F-FDG PET as a non-invasive and early predictor of efficacy to this new approach to targeting GBM metabolism. The studies proposed in this application present a new combination strategy through specific manipulation of metabolism and apoptotic pathways in malignant glioma and have the long-term potential to shift current approaches in glioma therapy.