Metabolic Imaging of Brain Tumor Response to Therapy

 描述（由申请人提供）：神经胶质瘤比任何其他癌症类型导致的寿命损失更多。 GBM 是最具侵袭性的神经胶质瘤形式，而少突胶质细胞瘤 (oligo) 和星形细胞瘤 (astro) 肿瘤的特点是生长速度较慢且生存期较长。然而，它们影响较年轻的人群，并且由于它们具有高度侵入性，几乎都会导致患者死亡。因此，人们越来越关注对寡核苷酸和天文患者进行更积极的治疗。特别是替莫唑胺 (TMZ) 和 PI3K 通路抑制剂 (PI3Kis) 目前正在进行临床试验。然而，寡聚肿瘤和星形肿瘤的成像并监测其对治疗的反应可能具有挑战性，需要新的方法。本研究的目的是识别并从机制上验证基于磁共振波谱 (MRS) 的代谢成像生物标志物，显示寡核苷酸和 astro 对治疗的反应。我们的初步 MRS 数据表明，TMZ 或 PI3Kis 治疗可调节三羧酸 (TCA) 循环通量以及细胞内谷氨酸和谷氨酰胺水平，但不会影响乳酸产生，这与基因表达数据一致，表明 TCA 循环在寡核苷酸和 astros 中发挥核心作用，但不影响乳酸合成。此外，我们的初步数据显示，在 TMZ 处理的细胞中，超极化葡萄糖产生的 6-磷酸葡萄糖酸水平升高，表明戊糖磷酸途径的通量增加。因此，我们假设 TCA 循环和磷酸戊糖途径的代谢成像可以帮助了解寡核苷酸和星体对治疗的反应。基于这一假设，我们建议研究最近开发的独特的遗传特征的患者源性寡核苷酸和 astro 模型，并通过以下目标开发新的 MRS 治疗反应生物标志物。目标 1. 确定神经球模型中少突胶质细胞瘤和星形细胞瘤对治疗反应的 1H 和 HP 13C MRS 生物标志物。我们将研究对照和处理过的oligo和astro神经球，以及GBM神经球，并使用1H和HP 13C MRS来识别代谢改变，以了解oligo和astro对TMZ或PI3Kis的反应。目标 2. 通过监测体内原位肿瘤的治疗反应来确定 1H 和 HP 13C MRS 生物标志物的翻译价值。我们将研究对照和治疗的oligo和astro荷瘤小鼠，并确定目标1中确定的1H和HP 13C MRS生物标志物的值，以告知药物靶标结合并预测对TMZ或PI3Kis治疗的反应。目标 3. 通过将代谢结果与药物作用机械地联系起来来验证代谢生物标志物。我们将研究来自 Aim 1 的神经球和来自 Aim 2 的切除肿瘤，并使用生化和细胞生物学测定法通过确定治疗调节的潜在机制来验证我们的成像生物标志物。

 DESCRIPTION (provided by applicant): Gliomas result in more years of life lost than any other cancer type. GBM is the most aggressive form of glioma, whereas oligodendroglioma (oligo) and astrocytoma (astro) tumors are characterized by a slower growth rate and longer survival. However, they affect a younger population and, because they are highly invasive, almost uniformly result in patient death. There is therefore an increasing focus on more aggressive treatments for oligo and astro patients. In particular, temozolomide (TMZ) and PI3K pathway inhibitors (PI3Kis) are currently in clinical trials. However, imaging of oligo and astro tumors and monitoring their response to therapy can be challenging, and new approaches are needed. The goal of this study is to identify and mechanistically validate magnetic resonance spectroscopy (MRS) - based metabolic imaging biomarkers of oligo and astro response to therapy. Our preliminary MRS data indicate that treatment with TMZ or PI3Kis leads to modulation of tricarboxylic acid (TCA) cycle flux and intracellular glutamate and glutamine levels but does not affect lactate production, consistent with gene expression data indicating a central role for the TCA cycle, but not for lactate synthesis, in oligos and astros. In addition, our preliminary data show that in TMZ-treated cells 6-phosphogluconate levels produced from hyperpolarized glucose are elevated, indicating an increase in flux towards the pentose phosphate pathway. We therefore hypothesize that metabolic imaging of the TCA cycle and pentose phosphate pathway can serve to inform on oligo and astro response to therapy. Based on this hypothesis we propose to investigate unique recently developed genetically characterized patient-derived oligo and astro models, and to develop new MRS biomarkers of response to treatment via the following Aims. Aim 1. To identify 1H and HP 13C MRS biomarkers of oligodendroglioma and astrocytoma response to therapy in neurosphere models. We will investigate control and treated oligo and astro neurospheres, as well as GBM neurospheres, and use 1H and HP 13C MRS to identify metabolic alterations that inform on oligo and astro response to TMZ or PI3Kis. Aim 2. To determine the translational value of 1H and HP 13C MRS biomarkers by monitoring therapeutic response in orthotopic tumors in vivo. We will investigate control and treated oligo and astro tumor-bearing mice and determine the value of 1H and HP 13C MRS biomarkers identified in Aim 1 to inform on drug-target engagement and predict response to therapy with TMZ or PI3Kis. Aim 3. To validate the metabolic biomarkers by mechanistically linking metabolic findings with drug action. We will investigate neurospheres from Aim 1 and excised tumors from Aim 2 and use biochemical and cell biological assays to validate our imaging biomarkers by determining the underlying mechanism for their modulation by treatment.