Project 2: Targeting metabolic vulnerabilities in glioblastoma

项目 2：针对胶质母细胞瘤的代谢脆弱性

基本信息

批准号：
10225551
负责人：
David A. Nathanson
金额：
$ 33.43万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
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/10225551
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 efficacy evaluation glucose metabolism glucose uptake in vivo molecular imaging neoplastic cell new combination therapies novel novel strategies novel therapeutic intervention 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

项目摘要

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脆弱性摘要/摘要胶质母细胞瘤（GBM）是所有癌症中最致命的一种，因此，新的治疗策略正在出现。我们和其他人已经证明，代谢重编程是 GBM 的一个关键特征。满足丰富的能量、营养和氧化还原需求，以支持肿瘤生长和存活。这种代谢重编程最突出的特征是向高糖酵解通量的转变。有证据表明，致癌信号传导可调节 GBM 中的糖酵解通量，从而抑制 GBM 的糖酵解通量。致癌信号可以破坏糖酵解，导致细胞能量代谢中间体减少然而，针对 GBM 中癌基因调节的糖酵解的治疗潜力。我们提供令人信服的初步数据，证明 EGFR 的急性抑制—— GBM 中最常改变的癌基因 - 可以快速有效地减弱葡萄糖摄取，因此，GBM 模型显示，由于这种“改变”的代谢状态，GBM 中的糖酵解通量增加。我们还证明了 18F-氟脱氧葡萄糖 (FDG) 对药理学 p53 激活的协同致死作用。正电子发射断层扫描 (PET) 可用作快速（数小时内）、非侵入性生物标记物，可以预测对这种新组合方法的敏感性。在本提案中，我们扩展了这些令人兴奋的内容。在目标 1 中，我们将研究是否联合靶向 EGFR 调节的糖酵解。（例如脉冲厄洛替尼）和 p53 激活（例如 Idasanutlin）在直接来自患者的原位治疗中有效我们还将确定 18F-FDG PET 是否可以作为 GBM 异种移植物的稳健预测生物标志物。在目标 2 中，我们建议探究该药物组合的潜在机制。 p53 在药理糖酵解减弱作用下引发细胞凋亡的意外作用最后，在目标 3 中，我们提出了一项临床试验来测试 EGFR 抑制是否与新型 p53 激活剂（Idasanutlin，由罗氏 (Roche) 提供的药物对于复发性 GBM 患者是安全有效的。评估 18F-FDG PET 作为这种新靶向方法疗效的非侵入性早期预测因子 GBM 代谢提出了一种新的组合策略。对恶性胶质瘤代谢和细胞凋亡途径的特异性调控，并具有长期效果有可能改变当前神经胶质瘤治疗方法。