Targeting metabolic vulnerabilities induced by the 1p19q codeletion in oligodendrogliomas

项目总结 胶质瘤是成人最常见的原发恶性脑肿瘤。在突变型胶质瘤中 异柠檬酸脱氢酶，包含1p/19q共缺失的肿瘤被归类为少突胶质细胞瘤。当前 放射和化疗等疗法毒性很大，会导致持久的、改变生命的缺陷。 在认知和身体能力上。重要的是，尽管少突胶质瘤患者在标准情况下存活多年 治疗后，肿瘤难免复发并导致病人死亡。由于1p/19q共缺失是 少突胶质细胞瘤，识别与1p/19共缺失相关的代谢易感性可导致 少突胶质瘤患者的精准药物。尤其是糖酵解代谢，促进了生物合成和 生物能量学，是肿瘤增殖的中心。糖酵解基因烯醇化酶1，位于 染色体1p36.23在少突胶质细胞瘤中由于1p/19q共缺失而丢失，留下这些肿瘤 持续的糖酵解依赖于烯醇化酶2(ENO2)。我们的研究表明，通过一种 安全、有效的ENO2抑制剂(POMHEX)下调患者来源的少突胶质细胞瘤的糖酵解。 然而，抑制ENO2会导致关键的丙酮酸脱氢酶(PDH)的代偿激活 三羧酸(TCA)循环酶。重要的是，将POMHEX与新型安全的PDH抑制剂CPI- 613完全阻止糖酵解、TCA循环和少突胶质细胞瘤的生长。因此，我们将测试 假设靶向ENO2和PDH是治疗少突胶质细胞瘤的精确治疗策略(目标1)。 新疗法的成功翻译受到缺乏相关生物标记物的阻碍 对治疗的反应。磁共振成像是胶质瘤成像的支柱，但无法准确地 关于治疗反应的报告。给药后的氢气磁共振波谱(DMRS) 葡萄糖等2H标记底物是一种安全的临床可翻译的糖酵解通量成像方法。 活着。在目标2中，我们将检查2H-葡萄糖报告对ENO2和PDH抑制的反应的能力。 临床相关场强(3T)下的体内少突胶质细胞瘤。 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 在这个基因组医学时代，少突胶质瘤。由于POMHEX和CPI-613的安全性已被 建立在灵长类动物和人类身上，而且由于DMRS可以很容易地部署在临床磁共振扫描仪上，我们的 治疗方法和伴随的生物标记物有可能迅速转化为临床。从本质上讲，通过 同时针对治疗和成像治疗反应的新陈代谢，我们的研究将使 改善少突胶质瘤患者预后和生活质量的精准医学。

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.