Non-invasive Assessment of Skeletal Muscle Loss in Cancer Patients

描述（由申请人提供）：本研究的长期目标是开发一种非侵入性方法，用于早期评估癌症患者新生3MH产生，作为评估哪些患者未来骨骼肌萎缩高风险的一种方法。该方法是基于已知的3-甲基组氨酸（3MH）在这一癌症患者亚群中从头产生的速率常数的增加，这是它们独特的肿瘤-宿主相互作用的结果。因此，我们假设，在摄入单次口服氘化3-甲基组氨酸（D-3MH）后，同位素衰变曲线末端部分的速率常数可以准确测量这种增加的风险，并且该速率常数可以通过在此期间获得的定时现场尿液样本进行无创测量。此外，我们假设在给药之前食用含3MH的食物不会对结果产生不利影响，从而使整个过程具有临床相关性。在第一阶段，我们将通过测试以下假设来确定我们的全面方法的可行性：(I)现场尿液样本中的同位素富集与相应的血浆样本相同，（ii）在给药时间之前和包括给药时间在内的肉类摄入量不会影响同位素衰变曲线末端部分的斜率。测试这两个假设的有效性是第一阶段研究的中心重点，对于开发一种既科学合理又无创且临床相关的方法至关重要。我们将在10名健康的老年男性志愿者身上测试我们方法的可行性。如果i期试验成功，我们建议在ii期资助下进行一项统计上强有力的前瞻性调查，以证明在新诊断的肺癌和胃肠道癌症患者中进行的这项试验可以预测肌肉萎缩的未来发展。我们期待i期和ii期联合研究的结果将导致生产和销售一种合适的“测试试剂盒”，用于早期识别高危癌症患者肌肉蛋白水解增加，以便进行医疗干预，防止未来的肌肉萎缩。

DESCRIPTION (provided by applicant): The long-term objective of this research is to develop a non-invasive approach for early assessment of de novo 3MH production in cancer patients as a way of assessing which patients are at high risk for future development of skeletal muscle atrophy. The approach is based on the known increase in the rate constant for de novo production of 3-methylhistidine (3MH) in this sub-set of cancer patients as a consequence of their unique tumor-host interactions. As such, we hypothesize that the rate constant for the terminal portion of the isotope decay curve following ingestion of a single oral dose of deuterated-3-methylhistidine (D-3MH) provides an accurate measure of this increased risk and that this rate constant can be measured non-invasively from timed spot urine samples obtained during this period. Furthermore, we hypothesize that consumption of 3MH- containing meals up to the time of dosing will not adversely affect the results making the entire procedure clinically relevant. During Phase I, we will establish the feasibility of our over all approach by testing the following hypotheses: (i) isotope enrichment in spot urine samples is identical with the corresponding plasma samples, and (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. Testing the validity of these two hypotheses is the central focus of the Phase-I research and is crucial to the development of an approach that is both scientifically sound as well as non-invasive and clinically relevant. We will test the feasibility of our approach in ten healthy older adult male volunteers. If Phase-I testing is successful, we propose, with Phase-II funding, to conduct a statistically powerful prospective investigation to demonstrate that this test conducted in newly diagnosed lung and gastrointestinal 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 increased muscle proteolysis in at-risk cancer patients so that medical intervention can take place and prevent future muscle atrophy. Project Narrative: Skeletal muscle loss is an important, but unpredictable, occurrence in patients with different types of cancer. Clinically significant skeletal muscle loss cannot be reversed and has poor prognostic implications. Its early assessment is important because it would permit selection of cancer patients for preventive strategies. The purpose of this project is to develop a non-invasive method for early assessment of increased skeletal muscle degradation in patients with cancer. 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 muscle loss 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 dinner.