Metabolic Imaging of Brain Tumor Response to Therapy

 描述(由申请人提供)：胶质瘤比任何其他类型的癌症导致更多的寿命损失。基底节细胞瘤是最具侵袭性的胶质瘤，而少突胶质细胞瘤和星形细胞瘤的特点是生长速度较慢，生存时间较长。然而，它们影响的是较年轻的人群，而且由于它们具有高度侵袭性，几乎都会导致患者死亡。因此，越来越多的人关注对寡妇和天文病人进行更积极的治疗。特别是替莫唑胺(TMZ)和PI3K途径抑制剂(PI3Kis)目前正在进行临床试验。然而，寡头和星形肿瘤的成像和监测它们对治疗的反应可能是具有挑战性的，需要新的方法。这项研究的目标是识别和机械验证基于磁共振波谱(MRS)的代谢成像生物标记物对治疗的寡聚和天文反应。我们的初步MRS数据表明，TMZ或PI3Kis治疗导致三羧酸(TCA)循环通量以及细胞内谷氨酸和谷氨酰胺水平的调节，但不影响乳酸的产生，这与基因表达数据一致，表明TCA循环在寡头和Astros中起中心作用，但对乳酸合成没有影响。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，表明流向戊糖磷酸途径的流量增加。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聚和天文对治疗的反应。基于这一假设，我们建议研究最近开发的独特的、具有遗传特征的患者来源的寡聚和ASTO模型，并通过以下目标开发新的MRS生物标记物来评价治疗效果。目的1.在神经球模型中鉴定少突胶质细胞瘤和星形细胞瘤的~1H和Hp~(13)C MRS生物标志物。我们将研究对照和治疗的寡聚和天文神经球，以及GBM神经球，并使用1H和HP 13C MRS来识别影响TMZ或PI3Kis的寡聚和天文反应的代谢变化。目的2.通过监测体内原位肿瘤的治疗反应，确定1H和Hp 13C MRS生物标志物的翻译价值。我们将调查对照和治疗的寡聚和Asto荷瘤小鼠，并确定Aim 1中确定的1H和Hp 13C MRS生物标记物的价值，以告知药物靶标接触并预测TMZ或PI3Kis治疗的反应。目的3.通过将代谢结果与药物作用机械地联系起来，验证代谢生物标记物。我们将研究AIM 1中的神经球和AIM 2中切除的肿瘤，并使用生化和细胞生物学分析来验证我们的成像生物标记物，确定它们通过治疗调节的潜在机制。

 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.