Project 2: Targeting metabolic vulnerabilities in glioblastoma

项目 2：针对胶质母细胞瘤的代谢脆弱性

• 批准号: 9983048
• 负责人: David A. Nathanson
• 金额: $ 34.16万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-11 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9983048
• 关键词: Achievement; Acute; Apoptosis; Apoptotic; Attenuated; BCL1 Oncogene; BCL2 gene; Biological Markers; Brain; Cells; Characteristics; Clinical Trials; Consumption; Data; Deletion Mutation; Dose; Drug Combinations; EGFR inhibition; Epidermal Growth Factor Receptor; Erlotinib; Evaluation; Exhibits; Family member; Glioblastoma; Glioma; Glucose; Glycolysis; Hour; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Maximum Tolerated Dose; Measurement; Metabolic; Metabolism; Modeling; Molecular; Nutrient; Oncogenes; Oncogenic; Oxidation-Reduction; Pathway interactions; Patients; Pharmacology; Phase; Phase I/II Clinical Trial; Positron-Emission Tomography; Pre-Clinical Model; Prediction of Response to Therapy; Process; Recurrence; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Stratification; TP53 gene; Testing; Therapeutic; Tumor Suppressor Proteins; Warburg Effect; Work; Xenograft procedure; analog; attenuation; glucose metabolism; glucose uptake; in vivo; molecular imaging; neoplastic cell; new combination therapies; novel; novel strategies; novel therapeutic intervention; novel therapeutics; patient stratification; patient subsets; phase 1 study; phase 2 study; predicting response; predictive marker; response; response biomarker; synergism; targeted treatment; tumor; tumor growth; tumor metabolism; uptake

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.

项目2：针对胶质母细胞瘤的代谢漏洞 总结/摘要 胶质母细胞瘤（GBM）是所有癌症中最致命的一种。因此，新的治疗策略是 迫切需要的。我们和其他人已经表明，代谢重编程是GBM的一个关键特征， 调节提高的能量、营养和氧化还原需求以支持肿瘤生长和存活。 这种代谢重编程的最突出特征是向高糖酵解通量的转变。最近 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GBM中癌基因调节的糖酵解的治疗潜力 仍然是个谜我们目前令人信服的初步数据表明，急性抑制EGFR - GBM中最常见的改变的癌基因-可以快速有效地减弱葡萄糖摄取， 因此，GBM中的糖酵解通量。由于这种“改变的”代谢状态，GBM模型显示， 协同致死药理学p53激活。我们还证明，18F-氟脱氧葡萄糖（FDG） 和正电子发射断层扫描（PET）可用作快速（数小时内），非侵入性生物标志物， 可以预测对这种新的组合方法的敏感性。在这份提案中，我们扩展了这些令人兴奋的 初步调查结果。在目标1中，我们将研究是否联合靶向EGFR调节的糖酵解， (e.g.,脉冲厄洛替尼）和p53激活（例如，Idasanutlin）在直接来自患者的原位 GBM异种移植物。我们还将确定18F-FDG PET是否可以作为一个强大的预测生物标志物， 对这种药物组合的敏感性。在目标2中，我们建议询问 p53在药理学糖酵解衰减下引发细胞凋亡中的意想不到的作用。最后，在目标3中， 我们提出了一项临床试验来测试EGFR抑制与新的p53激活剂（Idasanutlin， 由RocheTM提供）在复发性GBM患者中是安全有效的。纳入本试验的是 评价18F-FDG PET作为这种新靶向方法疗效的非侵入性和早期预测因子 GBM代谢。本申请中提出的研究提出了一种新的组合策略， 恶性胶质瘤中代谢和凋亡途径的特异性操纵， 有可能改变目前胶质瘤治疗的方法。