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Principal Investigator: Prakash Chinnaiyan
Organization: WILLIAM BEAUMONT HOSPITAL RESEARCH INST
Fiscal Year: 2024
Award: $323,500
Funding agency: National Institute of Neurological Disorders and Stroke
ABSTRACT
Glioblastoma (GBM) continues to be an invariably fatal malignancy with limited treatment options. Our
laboratory studies tumor metabolism and its potential to serve as a novel therapeutic target. Through a series
of investigations, our group has identified that the diverse tumor ecology implicit in this malignancy contributes
to considerable intratumoral metabolic heterogeneity and dynamic metabolic reprogramming, allowing GBM
cells to adapt and proliferate under diverse, microenvironmental stresses. Specifically, through integrative
cross-platform analyses coupling metabolomics with genomics in patient-derived tumors, we identified
enhanced fatty acid oxidization (FAO) as a metabolic node in GBM driven by a transcriptional program
designed to import and utilize fatty acids from the tumor microenvironment. This metabolic phenotype was
specific to the mesenchymal subtype in GBM and recapitulated in preclinical models. Functional analyses
uncovered specific roles these fatty acids play in gliomagenesis, which are dependent upon nutrient
availability. In a state of glucose deprivation, mesenchymal GBM cells utilize these exogenous fatty acids to
serve as a vital, alternate source of ATP, whereas in nutrient favorable conditions, the intermediary metabolism
of FAO acts as a metabolic cue to drive a transcriptional program supporting cellular proliferation and
mesenchymal differentiation. Accordingly, inhibiting FAO in standard, nutrient rich conditions led to decreased
proliferation, however, robust energetic stress and non-apoptotic cell death was observed in mesenchymal
GBM cells in the context of glucose deprivation. In this application, we propose to extend these promising
findings by defining molecular mechanisms governing enhanced FAO in GBM (Aim 1), delineating the multiple
roles FAO may play in gliomagenesis in the context of this tumor’s diverse tumor ecology (Aim 2), and evaluate
the translational potential for eliciting metabolic synthetic lethality in GBM through energetic stress (Aim 3).
Terms: <3 Hydroxybutyrate><Acylation><Automobile Driving><Bionomics><Cancer Treatment><Cancers><Cell Body><Cell Death><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cells><Cellular Proliferation><Chemicals><Clinical><Combined Modality Therapy><Complex><Coupling><Cues><D-Glucose><DNA Alteration><DNA Sequence Alteration><DNA mutation><Data><Development><Dextrose><Ecology><Energy-Generating Resources><Enzyme Gene><Enzymes><Event><Fatty Acid Metabolism Pathway><Fatty Acids><Gene Transcription><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genetic mutation><Genomics><Glioblastoma><Gliomagenesis><Glucose><Glycolysis><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><HDAC Agent><HDAC inhibitor><Heterogeneity><Histone Deacetylase Inhibitor><Histone deacetylase inhibition><Intermediary Metabolism><Investigation><Laboratory Study><Link><MMAC1><MMAC1 protein><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mediator><Mesenchymal><Mesenchymal Differentiation><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolism><Methods><Modeling><Molecular><Multimodal Therapy><Multimodal Treatment><Mutated in Multiple Advanced Cancers 1><Mutation><Nutrient><Nutrient availability><PHTS gene><PHTS protein><PTEN><PTEN gene><PTEN protein><PTEN1><PTK Receptors><Patients><Phenotype><Phosphatase and Tensin Homolog><Phosphatase and Tensin Homolog Deleted on Chromosome 10><Play><Pre-Clinical Model><Preclinical Models><Process><Proliferating><RNA Expression><Receptor Protein-Tyrosine Kinases><Receptor Tyrosine Kinase Gene><Research Design><Resistance><Role><Secondary to><Sequence Alteration><Series><Source><Stress><Study Type><Testing><Therapeutic><Toxic effect><Toxicities><Transcription><Transmembrane Receptor Protein Tyrosine Kinase><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptors><aggressive therapy><aggressive treatment><anti-cancer therapy><beta-Hydroxybutyrate><cancer cell metabolism><cancer metabolism><cancer microenvironment><cancer therapy><cancer-directed therapy><clinical relevance><clinically relevant><combination therapy><combinatorial><combined modality treatment><combined treatment><deprivation><design><designing><developmental><driving><energy source><fat metabolism><fatty acid metabolism><fatty acid-transport protein><genome mutation><genomic alteration><glioblastoma multiforme><glioma genesis><in vivo><lipid metabolism><malignancy><metabolic phenotype><metabolism measurement><metabolomics><metabonomics><metabotype><multi-modal therapy><multi-modal treatment><mutated in multiple advanced cancers 1 protein><necrocytosis><neoplasm/cancer><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><phosphatase and tensin homologue on chromosome ten><programs><resistant><social role><spongioblastoma multiforme><study design><translational opportunities><translational potential><treatment strategy><tumor><tumor cell metabolism><tumor metabolism><tumor microenvironment><uptake><β-Hydroxybutyrate>