Metabolic Imaging of Brain Tumor Response to Therapy

脑肿瘤治疗反应的代谢成像

• 批准号: 9249001
• 负责人: Sabrina Miriam Ronen
• 金额: $ 63.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249001
• 关键词: 6-phosphogluconate; Affect; Aftercare; Age; Asses; Biochemical; Biological Assay; Biological Markers; Brain Neoplasms; Caring; Cells; Cessation of life; Citric Acid Cycle; Clinical Trials; Communities; Data; Diagnosis; Drug Targeting; Drug effect disorder; Edema; Enhancing Lesion; Gadolinium; Gene Expression; Glioblastoma; Glioma; Glucose; Glutamates; Glutamine; Goals; Growth; Image; Isocitrate Dehydrogenase; Lead; Link; Liquid substance; Magnetic Resonance; Magnetic Resonance Spectroscopy; Malignant Neoplasms; Malignant neoplasm of brain; Metabolic; Modeling; Monitor; Mus; Mutation; Newly Diagnosed; Oligodendroglioma-Astrocytoma; Oligonucleotides; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pentosephosphate Pathway; Population; Production; Pyruvate; Recovery; Recurrent tumor; Research; Role; T2 weighted imaging; Treatment Efficacy; Tumor Markers; attenuation; base; cancer imaging; cancer type; imaging approach; imaging biomarker; imaging modality; improved; in vivo; inhibitor/antagonist; lactate dehydrogenase A; magnetic resonance spectroscopic imaging; metabolic imaging; neuro-oncology; novel; novel strategies; oligodendroglioma; precision medicine; predicting response; predictive marker; public health relevance; response; response biomarker; temozolomide; treatment effect; treatment response; tumor; years of life lost

 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.

 描述（由适用提供）：神经胶质瘤导致生命损失的年份比任何其他癌症类型都要多。 GBM是神经胶质瘤最具侵略性的形式，而少突胶质瘤（Oligo）和星形胶质细胞瘤（Astro）肿瘤的特征是生长速度缓慢和较长的存活率。但是，它们会影响年轻的人群，并且因为它们具有高度侵入性，几乎均匀地导致患者死亡。因此，越来越多的重点是为寡做和Astro患者进行更具侵略性的治疗。特别是，目前正在临床试验中，替莫唑胺（TMZ）和PI3K途径抑制剂（PI3KI）目前正在进行临床试验中。但是，可能会挑战寡核和天星肿瘤的成像以及监测其对治疗的反应，并且需要新的方法。这项研究的目的是鉴定和机械验证磁共振光谱法（MRS） - 基于寡磷的代谢成像生物标志物和Astro对治疗的反应。我们的初步MRS数据表明，用TMZ或PI3KI治疗会导致调节三核酸（TCA）周期通量和细胞内谷氨酸和谷氨酰胺水平的调节，但不影响乳酸产生，与TCA周期的基因表达相一致，但指示TCA周期的核心作用，但不是乳酸化的Oligos和Astros和Astros和Astros。此外，我们的初步数据表明，在TMZ处理的细胞中，由超极化葡萄糖产生的6-磷酸葡萄糖水平升高，表明向戊糖磷酸盐途径的通量增加。因此，我们假设TCA循环和五磷酸五磷酸五磷酸五循环的代谢成像可以用于寡核酸和Astro对治疗的反应。基于这一假设，我们建议研究最近开发的遗传特征的患者衍生的寡核能和Astro模型，并通过以下目的开发新的MRS生物标志物对治疗的反应。目的1。识别少突胶质瘤的1H和HP 13C生物标志物在神经圈模型中对治疗的反应。我们将研究对照和处理的寡磷和Astro神经球，以及GBM神经球，并使用1H和HP 13C MRS鉴定代谢变化，这些代谢变量涉及寡核酸和Astro对TMZ或PI3KIS的反应。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生物标志物的翻译值。我们将研究对照和治疗含有Astro肿瘤的小鼠，并确定AIM 1中确定的1H和HP 13C MRS生物标志物的值，以告知药物目标参与并预测对使用TMZ或PI3KIS治疗的反应。目的3。通过将代谢发现与药物作用联系起来来验证代谢生物标志物。我们将通过AIM 1和来自AIM 2的优秀肿瘤进行神经球，并使用生化和细胞生物学测定方法来通过确定通过治疗调节的基本机制来验证我们的成像生物标志物。