Non-invasive Assessment of Skeletal Muscle Loss in Cancer Patients

癌症患者骨骼肌损失的无创评估

• 批准号: 8314779
• 负责人: MORTEZA JANGHORBANI
• 金额: $ 30.38万
• 依托单位: BIOCHEMANALYSIS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-05 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8314779
• 关键词: 3-methylhistidine; Adult; Affect; Cancer Patient; Catabolism; Consumption; Development; Disease; Dose; Early identification; Excretory function; Future; Health; Hour; Individual; Intake; Intervention; Investigation; Isotopes; Lead; Marketing; Measurement; Measures; Meat; Medical; Methods; Muscle; Muscle Development; Muscle Proteins; Muscular Atrophy; Newly Diagnosed; Oral; Outcome; Patients; Phase; Plasma; Procedures; Production; Research; Risk; Sampling; Skeletal Muscle; Spottings; Testing; Time; Tracer; Urine; abstracting; base; clinically relevant; high risk; in vivo; male; prevent; prospective; protein degradation; sound; wasting

DESCRIPTION (provided by applicant): Abstract The long-term objective of this research is to develop a non-invasive approach for assessment of de novo 3MH production in cancer patients early in the course of the disease as a way of assessing which patients are at high risk for future development of skeletal muscle atrophy. The approach is based on: 1) the known increase in de novo production of 3-methylhistidine (3MH) from muscle protein breakdown in said patients as a consequence of their unique disease-host interactions, and 2) earlier demonstration that de novo 3MH production can be measured in vivo using isotope dilution. We envision a relatively simple method that is totally non-invasive yet able to assess the course of skeletal muscle loss in cancer patients. The approach depends on the hypothesis that after an oral dose of deuterated 3-methylhistidine (D-3MH), the slope of the terminal portion of the decay curve (> 12 hours post-dosing) for the tracer/tracee (D-3MH/3MH) in the free 3MH pool is directly proportional to the rate constant for myofibrillar protein degradation and can be determined from spot urine samples. During our Phase I research we established the feasibility of our overall approach by testing the following hypotheses in nine healthy adult males (four young, five older) by showing: (i) isotope enrichment in spot urine samples is identical with the corresponding plasma samples, (ii) meat intake up to and including the time of dosing does not influence the slope of the terminal portion of the isotope decay curve, and (iii) that the method is sufficiently sensitive to measure differences in the rate of 3MH production between young and older individuals. Testing the validity of these hypotheses was the central focus of the Phase-I research and crucial to the development of an approach that is both scientifically sound as well as non-invasive and clinically relevant. During Phase-II, we propose to conduct a statistically powerful prospective investigation to demonstrate that measurement of slope of the terminal decay curve (rate constant) with our approach in newly diagnosed cancer patients predicts future development of muscle wasting. We expect the outcome of the combined Phase-I and Phase-II research to lead to the manufacture and marketing of a suitable "Test Kit" for early identification of elevated muscle catabolism in at-risk patients so that medical intervention can take place and prevent future muscle atrophy. PUBLIC HEALTH RELEVANCE: Project Narrative Skeletal muscle loss is an important, but unpredictable, occurrence in many patients with different types of cancer and other chronic diseases. Early assessment is important because it would permit selection of high risk patients for preventive strategies. Once a clinically significant amount of skeletal muscle is lost in these patients it cannot be reversed and has poor prognostic implications. The purpose of this project is to develop a non-invasive method for early assessment of increased skeletal muscle degradation in non-small cell lung cancer patients. As a group, these patients have a high likelihood of weight- and skeletal muscle loss, but the results are expected to be applicable to other cancer types in which weight-loss is an important component. Our approach is based on development of a (non-radioactive) stable isotope tracer approach to permit accurate quantitative measurement of skeletal muscle degradation early in the course of the disease by monitoring spot urine samples for the ratio of labeled/unlabeled 3-methylhistidine the morning after consuming a small amount of labeled 3-methylhistidine along with a meat-free dinner.

描述（由申请人提供）： 摘要本研究的长期目标是开发一种非侵入性的方法，用于评估癌症患者在疾病早期的从头3 MH产生，作为评估哪些患者未来发展为骨骼肌萎缩的高风险的一种方式。该方法基于：1）已知在所述患者中由于其独特的疾病-宿主相互作用，由肌肉蛋白质分解重新产生3-甲基组氨酸（3 MH）的增加，和2）早期证明可以使用同位素稀释在体内测量重新产生3 MH。我们设想了一种相对简单的方法，完全无创，但能够评估癌症患者骨骼肌损失的过程。该方法依赖于以下假设：口服剂量的氘代3-甲基组氨酸（D-3 MH）后，游离3 MH库中示踪剂/示踪剂（D-3 MH/3 MH）的衰减曲线末端部分（给药后> 12小时）的斜率与肌原纤维蛋白降解的速率常数成正比，并且可以从现场尿样中确定。在我们的第一阶段研究中，我们通过在9名健康成年男性中测试以下假设，确定了我们整体方法的可行性（四个年轻的，五个年长的）通过展示：（i）现场尿液样品中的同位素富集与相应的血浆样品相同，（ii）直到并包括给药时间的肉类摄入不影响同位素衰变曲线的末端部分的斜率，及（iii）该方法对以下各项足够敏感 测量年轻人和老年人之间3 MH产生速率的差异。测试这些假设的有效性是第一阶段研究的中心焦点，对于开发一种既科学合理又无创和临床相关的方法至关重要。在第二阶段，我们建议进行一项统计学上强大的前瞻性研究，以证明在新诊断的癌症患者中使用我们的方法测量终末衰减曲线（速率常数）的斜率可预测未来肌肉萎缩的发展。我们预计，I期和II期研究的结果将导致合适的“测试试剂盒”的生产和销售，用于早期识别高危患者的肌钙蛋白升高，以便进行医疗干预并预防未来的肌肉萎缩。 公共卫生关系： 骨骼肌损失是一个重要的，但不可预测的，发生在许多不同类型的癌症和其他慢性疾病的患者。早期评估很重要，因为它可以选择高风险患者进行预防策略。一旦临床上显著量的骨骼肌在这些患者中丢失，则其不能逆转并且具有不良预后意义。本项目的目的是开发一种非侵入性的方法，用于早期评估非小细胞肺癌患者骨骼肌退化的增加。作为一个群体，这些患者有很高的可能性体重和骨骼肌损失，但结果预计将适用于其他癌症类型，其中体重减轻是一个重要组成部分。我们的方法是基于一种（非放射性）稳定同位素示踪方法的发展，以允许在疾病过程中的早期通过监测标记/未标记的3-甲基组氨酸的比例标记/未标记的3-甲基组氨酸早晨后消耗少量标记的3-甲基组氨酸沿着无肉晚餐的现场尿液样本的骨骼肌降解的准确定量测量。