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Targeting metabolic vulnerabilities induced by the 1p19q codeletion in oligodendrogliomas

针对少突胶质细胞瘤中 1p19q 编码缺失引起的代谢脆弱性

基本信息

批准号：
10722255
负责人：
Pavithra Viswanath
金额：
$ 18.88万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-25 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10722255
关键词：
19q 1p36 Adult Anabolism Astrocytes Astrocytoma Bioenergetics Biological Assay Biological Markers Brain Neoplasms Cancer Patient Cells Cessation of life Chemotherapy and/or radiation Chromosomes Citric Acid Cycle Classification Clinic Clinical Cognitive Cognitive deficits Colon Carcinoma Combined Modality Therapy Companions Compensation Deuterium Development Drug Kinetics Enzymes Genes Genomic medicine Genomics Glioma Glucose Glycolysis Goals Growth Human Image Isocitrate Dehydrogenase Label Life Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of liver Mass Spectrum Analysis Metabolic Metabolism Modeling Molecular Molecular Genetics Mus Mutation Neuroblastoma Oncology Outcome Oxidation-Reduction Patients Phosphoenolpyruvate Precision therapeutics Primary Brain Neoplasms Primates Production Proliferating Protein Isoforms Quality of life Recurrence Reporting Safety Specificity Testing Therapeutic Translating Translations brain tissue clinical translation clinically relevant enolase genetic signature glucose metabolism imaging biomarker imaging modality improved outcome in vivo inhibitor innovation malignant breast neoplasm metabolic imaging metabolomics mutant non-invasive imaging novel novel therapeutics oligodendroglioma phosphoglycerate precision medicine pyruvate dehydrogenase rational design response standard care treatment response tumor

项目摘要

PROJECT SUMMARY Gliomas are the most common malignant primary brain tumors in adults. Among gliomas driven by mutant isocitrate dehydrogenase, tumors harboring a 1p/19q codeletion are classified as oligodendrogliomas. Current therapies such as radiation and chemotherapy are highly toxic and cause long-lasting and life-altering deficits in cognitive and physical abilities. Importantly, although oligodendroglioma patients live for years with standard treatment, tumors inevitably recur and cause patient death. Since the 1p/19q codeletion is a hallmark of oligodendrogliomas, identifying metabolic vulnerabilities associated with the 1p/19 codeletion can lead to precision medicines for oligodendroglioma patients. Glycolytic metabolism, in particular, fuels biosynthesis and bioenergetics and is central to tumor proliferation. The glycolytic gene enolase 1, which is located on chromosome 1p36.23, is lost in oligodendrogliomas due to the 1p/19q codeletion, leaving these tumors dependent on enolase 2 (ENO2) for continued glycolysis. Our studies indicate that inhibiting ENO2 using a safe, potent ENO2 inhibitor (POMHEX) downregulates glycolysis in patient-derived oligodendrogliomas. However, ENO2 inhibition leads to a compensatory activation of pyruvate dehydrogenase (PDH), a key tricarboxylic acid (TCA) cycle enzyme. Importantly, combining POMHEX with the novel safe PDH inhibitor CPI- 613 completely abrogates glycolysis, the TCA cycle and oligodendroglioma growth. We will, therefore, test the hypothesis that targeting ENO2 and PDH is a precision therapy strategy for oligodendrogliomas (Aim 1). Successful translation of novel therapies is hindered by the lack of companion biomarkers that report on response to therapy. Magnetic resonance imaging, which is the mainstay of glioma imaging, fails to accurately report on response to therapy. Deuterium Magnetic Resonance Spectroscopy (DMRS) following administration of 2H-labeled substrates such as glucose is a safe clinically translatable method of imaging glycolytic flux in vivo. In Aim 2, we will examine the ability of 2H-glucose to report on response to ENO2 and PDH inhibition in oligodendrogliomas in vivo at clinically relevant field strength (3T). Our proposal is innovative and impactful because it will validate ENO2 and PDH as precision targets for oligodendrogliomas in this era of genomic medicine. Since the safety of POMHEX and CPI-613 has been established in primates and humans, and since DMRS can be readily deployed on clinical MR scanners, our therapies and companion biomarkers have the potential to be rapidly translated to the clinic. In essence, by simultaneously targeting metabolism for therapy and for imaging treatment response, our studies will enable precision medicine that improves outcomes and quality of life for oligodendroglioma patients.

项目总结