Metabolic imaging comparisons of patient-derived models of renal cell carcinoma

肾细胞癌患者来源模型的代谢成像比较

基本信息

批准号：
9753176
负责人：
John Kurhanewicz
金额：
$ 62.63万
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：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9753176
关键词：
3-Dimensional American Apoptosis Biological Biological Assay Biological Markers Biological Models Bioreactors Cancer Model Cell Culture Techniques Cells Cessation of life Clear cell renal cell carcinoma Clinical Clinical Trials Complex DNA sequencing Data Detection Development Diagnosis Disease Enzymes Evaluation Excretory function Exhibits Fibrous capsule of kidney Frequencies Functional disorder Funding Opportunities Genes Genetic Genotype Glutaminase Glycolysis Gold Growth Image Imaging Techniques Implant Individual Label MET gene Magnetic Resonance Magnetic Resonance Imaging Malignant Neoplasms Metabolic Metabolic Pathway Metabolism Mission Modeling Monitor Mus Mutation Nuclear Nucleic Acids Organism Oxygen Pathologic Pathway interactions Patients Phenotype Physiological Processes Play Pre-Clinical Model Primary Cell Cultures Process Production Proteins Public Health Renal Cell Carcinoma Renal carcinoma Research Research Personnel Resistance Role Short Tandem Repeat Slice Specimen Techniques Testing Therapeutic Thinness Time Tissues United States National Institutes of Health Urogenital Cancer VHL gene Warburg Effect Xenograft procedure clinically relevant detection of nutrient enzyme activity established cell line exhibitions experience first-in-human genetic analysis human model imaging approach implantation improved in vitro Model inhibitor/antagonist lipid metabolism metabolic abnormality assessment metabolic imaging metabolic phenotype metabolic profile metabolomics molecular imaging mortality non-invasive imaging novel outcome forecast patient response response tissue culture transcriptome sequencing transcriptomics tumor metabolism tumor xenograft

项目摘要

This year, ~62,000 Americans will be diagnosed with kidney cancer and more than 14,000 individuals will die from this disease. Nine of ten kidney cancers are renal cell carcinoma (RCC). To reduce mortality from RCC, improvements are needed at all stages, from diagnosis to prognosis to therapy. In response to the funding opportunity “Biological Comparisons in Patient-derived Models of Cancer (U01)”, we will compare four types of patient-derived models of RCC to investigate the relative authenticity of each as a preclinical model. The first will be patient-derived xenografts (PDXs), widely perceived as the most representative models of human pathophysiology. These have been previously established from a range of pathologic and clinical stages of RCC. The PDXs will serve as the “gold standard” to which to compare three PDX-derived models, including tissue slice cultures (TSCs), primary cell cultures, and xenografts generated from cell cultures. The biological comparison on which we focus is metabolism. Dysregulated metabolism, one of the hallmarks of cancer, is strongly implicated in the development and progression of RCC. Pleiotropic changes include dysregulation of oxygen sensing, energy sensing and nutrient sensing. In particular, high frequency mutations in VHL and FBP1 genes contribute to exhibition of the “Warburg effect” (an elevation of glycolysis in the presence of oxygen) in clear cell RCC, the major subtype of RCC, leading to increased production and excretion of lactate. Comparing metabolism among the four patient-derived models of RCC will capture the functional consequences of genetic, transcriptomic, environmental and other influences to provide a comprehensive picture of the phenotype of each model system. We will use hyperpolarized (HP) 13C magnetic resonance (MR), a remarkably sensitive molecular imaging technique, to surveil dynamic pathway-specific metabolic and physiologic processes in the patient-derived RCC models, yielding biologically and clinically relevant data. Aim 1 will identify the metabolic signature of each of 8 RCC PDXs by HP MR imaging and steady state metabolomic profiling. The metabolic data will be associated with genotypic, transcriptomic and immunotypic features to establish the phenotype of each PDX. In Aim 2, thin precision-cut tissue slices will be prepared from each of the 8 PDXs and placed in a NMR-compatible, 3D tissue culture bioreactor. The metabolic phenotype of the TSCs will be determined by HP MR and steady state studies and compared to that of the original PDXs, along with genetic, transcriptomic and immunohistologic features. Similar studies will be performed in Aim 3 with primary cell cultures derived from PDXs, and in Aim 4 with xenografts generated by the implantation in mice of PDX-derived cell cultures. In Aim 5, the final test of the four types of models will be a comparison of metabolic responses to the clinically relevant glutaminase inhibitor CB-839, which is currently entering clinical trials in RCC.

今年，约 62,000 名美国人将被诊断出患有肾癌，超过 14,000 人将被诊断患有肾癌。十种肾癌中有九种是肾细胞癌 (RCC)。 RCC，从诊断到预后再到治疗的各个阶段都需要改进。资助机会“患者衍生癌症模型的生物学比较（U01）”，我们将比较四个类型的患者衍生肾细胞癌模型，以研究每种模型作为临床前模型的相对真实性。第一个是患者来源的异种移植物（PDX），被广泛认为是最具代表性的模型这些是先前根据一系列病理学和临床学建立的。 PDX 将作为比较三个 PDX 衍生模型的“黄金标准”，包括组织切片培养物 (TSC)、原代细胞培养物和由细胞培养物产生的异种移植物。我们关注的生物学比较是新陈代谢失调，这是其中之一。癌症的标志，与 RCC 的发生和进展密切相关。包括氧传感、能量传感和营养传感的失调，特别是高频。 VHL 和 FBP1 基因的突变有助于表现出“Warburg 效应”（糖酵解升高）透明细胞肾细胞癌（RCC 的主要亚型）中存在氧气），从而导致产量增加和比较四种源自患者的肾细胞癌模型的代谢情况将捕获乳酸的排泄。遗传、转录组、环境和其他影响的功能后果，以提供我们将使用超极化 (HP) 13C 磁性来全面了解每个模型系统的表型。共振 (MR) 是一种独特灵敏的分子成像技术，用于监测动态通路特异性源自患者的 RCC 模型中的代谢和生理过程，产生生物学和临床效果相关数据。目标 1 将通过 HP MR 成像和稳态识别 8 个 RCC PDX 中每一个的代谢特征代谢组学分析。代谢数据将与基因型、转录组学和免疫型相关。在目标 2 中，将制备薄的精密切割组织切片。来自 8 个 PDX 中的每一个，并放置在 NMR 兼容的 3D 组织培养生物反应器中。 TSC 的表型将通过 HP MR 和稳态研究确定，并与 TSC 的表型进行比较原始的 PDX 以及遗传、转录组和免疫组织学特征将进行类似的研究。在目标 3 中使用源自 PDX 的原代细胞培养物进行，在目标 4 中使用由 PDX 产生的异种移植物进行在目标 5 中，将 PDX 衍生细胞培养物植入小鼠体内，对四种模型进行最终测试。与临床相关谷氨酰胺酶抑制剂 CB-839 的代谢反应比较，该抑制剂目前正在研究中进入 RCC 临床试验。