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.

Public Health Relevance

Project 2: Targeting metabolic vulnerabilities in glioblastoma NARRATIVE The studies proposed herein aim to utilize targeted therapies for specific and rapid attenuation of tumor glucose consumption, thereby exposing targetable vulnerabilities to agents that stimulate tumor cell apoptosis (i.e., p53 activators) for synergistic lethality in malignant glioma. The incorporation of metabolic 18F-FDG positron emission tomography (PET) scanning will determine whether non-invasive molecular imaging can be used for early patient stratification to this new combination therapy for glioma patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Los Angeles
United States
Zip Code
Pope, Whitney B (2018) Brain metastases: neuroimaging. Handb Clin Neurol 149:89-112
Li, Tie; Cox, Christopher D; Ozer, Byram H et al. (2018) D-2-Hydroxyglutarate Is Necessary and Sufficient for Isocitrate Dehydrogenase 1 Mutant-Induced MIR148A Promoter Methylation. Mol Cancer Res 16:947-960
Kepe, Vladimir; Scafoglio, Claudio; Liu, Jie et al. (2018) Positron emission tomography of sodium glucose cotransport activity in high grade astrocytomas. J Neurooncol 138:557-569
Magaki, Shino; Parks, Robyn; Vinters, Harry V et al. (2018) A 44-Year-Old Female with Familial Mediterranean Fever, Cardiomyopathy and End Stage Renal Disease. Brain Pathol 28:135-136
Gallaher, Sean D; Fitz-Gibbon, Sorel T; Strenkert, Daniela et al. (2018) High-throughput sequencing of the chloroplast and mitochondrion of Chlamydomonas reinhardtii to generate improved de novo assemblies, analyze expression patterns and transcript speciation, and evaluate diversity among laboratory strains and wild isolates. Plant J 93:545-565
Calais, Jeremie; Czernin, Johannes; Cao, Minsong et al. (2018) 68Ga-PSMA-11 PET/CT Mapping of Prostate Cancer Biochemical Recurrence After Radical Prostatectomy in 270 Patients with a PSA Level of Less Than 1.0 ng/mL: Impact on Salvage Radiotherapy Planning. J Nucl Med 59:230-237
Liau, Linda M; Ashkan, Keyoumars; Tran, David D et al. (2018) First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. J Transl Med 16:142
Ellingson, Benjamin M; Wen, Patrick Y; Cloughesy, Timothy F (2018) Evidence and context of use for contrast enhancement as a surrogate of disease burden and treatment response in malignant glioma. Neuro Oncol 20:457-471
Ellingson, Benjamin M; Abrey, Lauren E; Nelson, Sarah J et al. (2018) Validation of postoperative residual contrast-enhancing tumor volume as an independent prognostic factor for overall survival in newly diagnosed glioblastoma. Neuro Oncol 20:1240-1250
Majedi, Fatemeh S; Hasani-Sadrabadi, Mohammad Mahdi; Kidani, Yoko et al. (2018) Cytokine Secreting Microparticles Engineer the Fate and the Effector Functions of T-Cells. Adv Mater 30:

Showing the most recent 10 out of 91 publications