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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA211015-04
Application #
9983048
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2017-08-11
Project End
2022-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Levin, Victor A; Ellingson, Benjamin M (2018) Understanding brain penetrance of anticancer drugs. Neuro Oncol 20:589-596
Ferguson, Sherise D; Zhou, Shouhao; Huse, Jason T et al. (2018) Targetable Gene Fusions Associate With the IDH Wild-Type Astrocytic Lineage in Adult Gliomas. J Neuropathol Exp Neurol 77:437-442
Ellingson, Benjamin M; Salamon, Noriko; Woodworth, Davis C et al. (2018) Reproducibility, temporal stability, and functional correlation of diffusion MR measurements within the spinal cord in patients with asymptomatic cervical stenosis or cervical myelopathy. J Neurosurg Spine 28:472-480
Kuo, Eric J; Sho, Shonan; Li, Ning et al. (2018) Risk Factors Associated With Reoperation and Disease-Specific Mortality in Patients With Medullary Thyroid Carcinoma. JAMA Surg 153:52-59
Kirsch, David G; Diehn, Max; Kesarwala, Aparna H et al. (2018) The Future of Radiobiology. J Natl Cancer Inst 110:329-340
Laks, Dan R; Oses-Prieto, Juan A; Alvarado, Alvaro G et al. (2018) A molecular cascade modulates MAP1B and confers resistance to mTOR inhibition in human glioblastoma. Neuro Oncol 20:764-775
Magaki, Shino; Tang, Zhaoyi; Tung, Spencer et al. (2018) The effects of cerebral amyloid angiopathy on integrity of the blood-brain barrier. Neurobiol Aging 70:70-77
Omuro, Antonio; Vlahovic, Gordana; Lim, Michael et al. (2018) Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143. Neuro Oncol 20:674-686
Magaki, Shino D; Williams, Christopher K; Vinters, Harry V (2018) Glial function (and dysfunction) in the normal & ischemic brain. Neuropharmacology 134:218-225
Woodworth, Davis C; Holly, Langston T; Mayer, Emeran A et al. (2018) Alterations in Cortical Thickness and Subcortical Volume are Associated With Neurological Symptoms and Neck Pain in Patients With Cervical Spondylosis. Neurosurgery :

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