Targeting metabolic vulnerabilities in glioblastoma

针对胶质母细胞瘤的代谢脆弱性

• 批准号: 10225454
• 负责人: David A. Nathanson
• 金额: $ 49.1万
• 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: 2017-08-07 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225454
• 关键词: Acute; Apoptosis; Apoptotic; Attenuated; Biological Markers; Brain; Cell membrane; Cells; Characteristics; Clinical; Clinical Trials; Collaborations; Companions; Consumption; Coupled; Data; Deletion Mutation; Dependence; Disease; Drug Combinations; Drug usage; EGFR inhibition; Epidermal Growth Factor Receptor; Erlotinib; Glioblastoma; Glioma; Glucose; Hour; Lesion; Link; Malignant Glioma; Malignant Neoplasms; Measurement; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Molecular; Molecular Profiling; Nutrient; Oncogenes; Oncogenic; Oxidation-Reduction; Pathogenesis; Pathway interactions; Patients; Pharmacology; Positron-Emission Tomography; Process; Prognosis; Proteins; Recurrence; SLC2A1 gene; Series; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Stratification; TP53 gene; Technology; Testing; Therapeutic; Tumor Suppressor Proteins; Work; Xenograft procedure; analog; attenuation; clinical efficacy; clinical translation; clinically relevant; combinatorial; experience; falls; fluorodeoxyglucose; glucose metabolism; glucose uptake; in vivo; molecular drug target; molecular imaging; molecular scale; new combination therapies; novel; novel strategies; novel therapeutic intervention; patient stratification; pharmacodynamic biomarker; pre-clinical; predicting response; predictive marker; response; response biomarker; synergism; targeted treatment; tumor; tumor growth; tumor progression

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.

胶质母细胞瘤是所有癌症中最致命的一种。因此，新的治疗策略是绝望的

项目成果

Hyaluronic-Acid Based Hydrogels for 3-Dimensional Culture of Patient-Derived Glioblastoma Cells.

用于患者来源的胶质母细胞瘤细胞三维培养的透明质酸水凝胶。

• DOI: 10.3791/58176
• 发表时间: 2018
• 期刊: Journal of visualized experiments : JoVE
• 作者: Xiao,Weikun;Ehsanipour,Arshia;Sohrabi,Alireza;Seidlits,StephanieK
• 通讯作者: Seidlits,StephanieK

Brain-Mimetic 3D Culture Platforms Allow Investigation of Cooperative Effects of Extracellular Matrix Features on Therapeutic Resistance in Glioblastoma.

拟脑 3D 培养平台可以研究细胞外基质特征对胶质母细胞瘤治疗耐药性的协同影响。

• DOI: 10.1158/0008-5472.can-17-2429
• 发表时间: 2018
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Xiao,Weikun;Zhang,Rongyu;Sohrabi,Alireza;Ehsanipour,Arshia;Sun,Songping;Liang,Jesse;Walthers,ChristopherM;Ta,Lisa;Nathanson,DavidA;Seidlits,StephanieK
• 通讯作者: Seidlits,StephanieK