Metabolic Imaging of Brain Tumor Response to Therapy

脑肿瘤治疗反应的代谢成像

基本信息

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
项目类别：
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

项目摘要

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（通过应用证明）：与其他癌症类型相比，Gliomas Res ROST是少突胶质瘤（Oligo）和星形胶质细胞瘤（Astro）的肿瘤的特征，其特征是较长的生存率和更长的生存率。寡素和素二唑酚（TMZ）和途径抑制剂（PI3KIS）目前正在临床试验中，寡素抑制剂（TMZ）和天文疗法的抑制剂（PI3KIS）。 IS研究是为了识别和机械性验证磁共振光谱（MRS）的代谢成像寡素的生物标志物和Astro对治疗的反应表达TCA循环的核心作用，但没有用于乳酸合成的数据，此外，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ANN的ANN增加了Flux Toss phoss可以通过以下目的来研究唯一的遗传特征性的寡素模型和Astro模型，并通过以下目标开发新的MRS生物标志物。 Astro神经螺旋体以及GBM神经球，并使用1H和HP 13C TMZ或PI3KIS。在AIM 1中识别出1H和HP 13C的甲基肿瘤和HP 13C的抗象征性，以告知药物标准英语，并通过机械上的机械性生物标志物来验证药物标准的英语。将代谢结果与AIM 1的药物作用联系起来，并使用生化和细胞生物学测定法来确定通过治疗调节的机制来验证我们的成像器。