Metabolic Imaging of Brain Tumor Response to Therapy

 描述（由申请人提供）：胶质瘤导致比任何其他癌症类型更多的寿命损失。GBM是胶质瘤的最具侵袭性的形式，而少突胶质细胞瘤（oligo）和星形细胞瘤（astro）肿瘤的特征在于生长速率较慢和存活时间较长。然而，它们影响年轻人群，并且由于它们具有高度侵入性，几乎一致地导致患者死亡。因此，越来越多的人关注对寡核苷酸和Astro患者进行更积极的治疗。特别是，替莫唑胺（TMZ）和PI 3 K通路抑制剂（PI 3 Kis）目前正在临床试验中。然而，寡核和星形肿瘤的成像和监测其对治疗的反应可能具有挑战性，需要新的方法。本研究的目的是确定和机制验证磁共振波谱（MRS）为基础的代谢成像生物标志物的寡和astro治疗反应。我们的初步MRS数据表明，TMZ或PI 3 Kis治疗导致三羧酸（TCA）循环流量和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，与基因表达数据一致，表明在寡核苷酸和阿斯特罗斯中，TCA循环发挥核心作用，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，由超极化葡萄糖产生的6-磷酸葡萄糖酸水平升高，表明流向磷酸戊糖途径的通量增加。因此，我们假设TCA循环和戊糖磷酸途径的代谢成像可以用于告知寡核苷酸和星形细胞对治疗的反应。基于这一假设，我们建议研究独特的最近开发的遗传特征的患者衍生的寡核苷酸和astro模型，并开发新的MRS生物标志物的治疗反应通过以下目的。目标1.在神经球模型中鉴定少突胶质细胞瘤和星形细胞瘤对治疗反应的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星形神经球，以及GBM神经球，并使用1H和HP 13 C MRS来鉴定代谢改变，这些改变告知寡聚和星形对TMZ或PI 3 Kis的反应。目标二。通过监测体内原位肿瘤的治疗反应，确定1H和HP 13 C MRS生物标志物的转化值。我们将研究对照和治疗的寡和星形肿瘤荷瘤小鼠，并确定目标1中鉴定的1H和HP 13 C MRS生物标志物的值，以告知药物靶点接合并预测对TMZ或PI 3 Kis治疗的反应。目标3：通过将代谢结果与药物作用机制联系起来，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，并使用生物化学和细胞生物学测定，通过确定治疗对其进行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.