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.

项目摘要神经胶质瘤是成人最常见的恶性原发性脑肿瘤。在突变体驱动的神经胶质瘤中异位酸脱氢酶，具有1p/19q codeletion的肿瘤被分类为寡胶质细胞瘤。当前的诸如放射和化学疗法等疗法有剧毒，并导致持久和改变生活的缺陷在认知和身体能力中。重要的是，尽管少突可瘤患者患有标准多年治疗，肿瘤不可避免地会复发并导致患者死亡。由于1p/19q codeletion是少突endrogliomas，识别与1p/19 codeletion相关的代谢漏洞可能导致少突可瘤患者的精密药物。特别是糖酵解代谢，促进生物合成和生物能学，对于肿瘤增殖至关重要。糖酵解基因烯醇酶1，位于 1p36.23染色体，由于1p/19q codeletion而在寡头胶质瘤中丢失，留下这些肿瘤取决于烯醇酶2（ENO2）进行持续糖酵解。我们的研究表明，使用A抑制ENO2 安全，有效的ENO2抑制剂（POMHEX）下调了患者衍生的寡糖瘤中的糖酵解。但是，ENO2抑制导致丙酮酸脱氢酶（PDH）的补偿性激活，钥匙三羧酸（TCA）循环酶。重要的是，将POMHEX与新型的安全PDH抑制剂CPI结合在一起 613完全消除了糖酵解，TCA循环和少突胶质瘤的生长。因此，我们将测试靶向ENO2和PDH是寡聚胶质瘤的精确疗法策略（AIM 1）的假设。由于缺乏报告的伴侣生物标志物的妨碍了新的疗法的成功翻译对治疗的反应。磁共振成像是神经胶质瘤成像的中流报告对治疗的反应。给药后，氘磁共振光谱（DMR） 2H标记的底物（例如葡萄糖）是一种可靠的临床翻译方法，可在体内。在AIM 2中，我们将研究2H-葡萄糖报告对ENO2和PDH抑制作用的能力在临床相关的田间强度（3T）的体内少突胶质瘤。我们的建议具有创新性和影响力，因为它将验证ENO2和PDH作为精确目标在这个基因组医学时代，少突endrogliomas。由于POMHEX和CPI-613的安全在灵长类动物和人类中建立，并且由于DMR可以很容易地部署在临床MR扫描仪上，所以我们疗法和伴侣生物标志物具有迅速转化为诊所的潜力。本质上，由同时将代谢用于治疗和成像治疗反应，我们的研究将实现精确药物改善少突可瘤患者的结局和生活质量。