Project 3: Clinically Actionable Biomarkers from Renal Cell Carcinoma Metabolism and Imaging

项目 3：肾细胞癌代谢和影像学中临床可行的生物标志物

• 批准号: 9071072
• 负责人: RALPH J DEBERARDINIS
• 金额: $ 30.03万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9071072
• 关键词: Aggressive behavior; Anabolism; Behavior; Benign; Biological; Biological Markers; Biology; Biopsy; Blood Vessels; Caring; Cell Proliferation; Cellularity; Clinical; Clinical Management; Complement; Data; Diagnosis; Diagnostic Neoplasm Staging; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Early Diagnosis; Engraftment; Enrollment; Enzymes; Excision; Exhibits; Fatty acid glycerol esters; Frequencies; Genes; Glucose; Glutaminase; Glutamine; Glutathione; Growth; Histologic; Histology; Human; Image; Imaging Techniques; Implant; Incidence; Indolent; Infusion procedures; Isotope Labeling; Kidney; Label; Lipids; Magnetic Resonance; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant - descriptor; Malignant Neoplasms; Measurement; Measures; Medical center; Metabolic; Metabolic Pathway; Metabolism; Molecular Genetics; Monitor; Mus; Mutate; Natural History; Nephrectomy; Nutrient; Observational Study; Operative Surgical Procedures; Oxidation-Reduction; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Phase I Clinical Trials; Positron-Emission Tomography; Process; Protocols documentation; Renal Cell Carcinoma; Renal Mass; Renal carcinoma; Reporting; Research Personnel; Spin Labels; Supporting Cell; Techniques; Testing; Texas; Therapeutic; Therapeutic Intervention; Time; Tissues; Translating; Tumor Biology; Tumor stage; Universities; Urine; Work; Xenograft procedure; angiogenesis; base; clinically actionable; clinically relevant; cohort; comparative; complement pathway; contrast enhanced; density; imaging biomarker; imaging modality; in vivo; inhibitor/antagonist; innovation; lipid biosynthesis; lipid metabolism; macromolecule; metabolome; metabolomics; mortality; mouse model; neoplastic cell; new therapeutic target; novel marker; novel therapeutics; patient stratification; patient subsets; pre-clinical; preclinical study; predictive marker; prevent; prospective; research study; surveillance study; targeted treatment; tumor; tumor growth; tumor progression; uptake

Project Summary This proposal is motivated by the principle that systematic analysis of Renal Cell Carcinoma (RCC) metabolism will produce biomarkers predicting oncological behavior and tumor-specific vulnerabilities against which to direct novel therapies. RCC is diagnosed with increasing frequency in asymptomatic patients due to the proliferation of cross-sectional imaging techniques. Although most small renal masses (SRMs) diagnosed in this manner are indolent, there are no clear criteria by which to predict whether a given mass will behave aggressively and require escalation of care. We propose to capitalize on altered RCC metabolism to identify predictive biomarkers correlating with oncological behavior in SRMs undergoing active surveillance (AS), and to identify a key set of reprogrammed metabolic activities whose function is required for aggressive RCC growth. The rationale for the project is as follows: 1) most genes mutated in RCC regulate metabolism at the cellular level; 2) metabolism is dynamic, quantifiable and responsive to many processes relevant to RCC biology and disease progression; 3) many of these processes can be monitored non-invasively through multiparametric magnetic resonance (mpMR) imaging; and 4) blockade of these metabolic activities should prevent tumor progression. We therefore hypothesize that rigorous metabolomics and imaging can be used to identify quantitative features that predict tumor aggressiveness in SRMs, and that can be inhibited to suppress the growth of aggressive RCC. We will pursue three aims to test this hypothesis, each featuring an integrated, innovative array of techniques developed by the outstanding group of investigators involved in this Project. Aims 1 and 2 will feature a prospective, observational study of 160 patients on AS for incidentally diagnosed SRMs. This cohort will be monitored longitudinally by mpMRI (Aim 1) and by metabolomics in the renal mass and urine (Aim 2). Patients who progress to surgical intervention because of accelerating tumor growth rates will have imaging and metabolomics repeated at the time of nephrectomy, and a subset of patients will receive intra-operative infusion of isotope-labeled nutrients to assess tumor metabolic flux in vivo (Aim 2). Data from the cohort will be analyzed to identify metabolomic and imaging features correlating with oncological aggression. In Aim 3, we will use metabolomics, metabolic flux analysis and multi-modality imaging (PET, MR) to identify metabolic features of aggressive RCC growth in a set of genetically and histologically diverse orthotopic RCC tumors in mice. Enzymes from key pathways differentiating tumor from normal kidney will be inhibited to determine the effect on tumor growth. Altogether, work in this Project will produce a comprehensive and dynamic view of reprogrammed metabolism in human RCC and will identify new metabolic candidates for targeted therapy. A key, unique deliverable, satisfying an important unmet clinical need in kidney cancer management, will be the discovery of a set of biomarkers with the potential to guide AS in patients with incidentally diagnosed SRMs.

项目摘要 这一建议的动机是对肾癌(RCC)代谢进行系统分析的原则 将产生预测肿瘤学行为和肿瘤特异性脆弱性的生物标记物 直接的新疗法。在无症状的患者中，肾细胞癌的诊断频率增加，原因是 横断面成像技术的激增。尽管大多数小肾脏肿块(SRM)在 这种方式是懒惰的，没有明确的标准来预测给定的质量是否会表现 非常积极，需要更多的护理。我们建议利用改变的RCC新陈代谢来识别 接受主动监测(AS)的SRM中与肿瘤行为相关的预测性生物标记物，以及 确定一组关键的重新编程的代谢活动，这些活动的功能是积极的肾癌所必需的 成长。该项目的基本原理如下：1)肾细胞癌中大多数突变的基因在 细胞水平；2)代谢是动态的、可量化的，并对许多与肾细胞癌相关的过程做出反应 生物学和疾病进展；3)这些过程中的许多可以通过 多参数磁共振(MpMR)成像；以及4)阻断这些代谢活动 防止肿瘤进展。因此，我们假设严格的代谢组学和成像技术可以用来 确定在SRM中预测肿瘤侵袭性的定量特征，以及可以抑制抑制的量化特征 积极进取的RCC的增长。我们将追求三个目标来验证这一假设，每个目标都具有一个集成的、 由参与该项目的杰出研究人员团队开发的一系列创新技术。 AIMS 1和2将对160名AS意外诊断患者进行前瞻性观察性研究 SRMS。这一队列将通过mpMRI(目标1)和肾脏肿块代谢组学进行纵向监测。 和尿液(目标2)。因肿瘤生长速度加快而进行手术干预的患者 将在肾脏切除时重复进行成像和代谢组学，部分患者将接受 术中输注同位素标记的营养物质以评估体内的肿瘤代谢通量(目标2)。数据来自 将对队列进行分析，以确定与肿瘤学相关的代谢和成像特征 攻击性。在目标3中，我们将使用代谢组学、代谢流量分析和多模式成像(PET、MR) 鉴定侵袭性肾细胞癌生长的代谢特征在一组遗传和组织学上不同的 小鼠原位肾细胞癌模型。区分肿瘤和正常肾脏的关键途径的酶将是 抑制以确定其对肿瘤生长的影响。总之，这个项目的工作将产生一个全面的 和动态观察人肾细胞癌中重新编程的代谢，并将确定新的代谢候选 靶向治疗。一种关键的、独特的交付方式，满足了肾癌患者尚未满足的重要临床需求 管理方面，将发现一组有潜力指导AS患者的生物标志物 偶然诊断为自发性肌萎缩侧索硬化症。