Plasma DSC for early detection of disease and therapeutic efficacy in melanoma

描述（由申请人提供）：IV期黑色素瘤每年在全球造成约40,000人死亡。早期发现新的转移瘤是至关重要的，因为多达三个转移性肿瘤可以切除以治愈，并且疾病负担有限的患者使用ipilimumab（抗CTLA4）等免疫治疗药物可以改善临床结果。因此，常规每3个月进行一次全身FDG-PET和CT成像评估以进行监测，每2个月进行一次反应评估。然而，这些扫描的效用受到成本和继发性恶性肿瘤累积辐射暴露的限制。因此，开发新的非侵入性黑素瘤检测和频繁监测方法有望显著减少与黑素瘤有关的死亡。我们研究的首要目标是发展血浆差示扫描量热法（DSC）分析，作为一种新的非侵入性诊断方法，以实现更频繁的监测，促进早期发现复发和早期评估治疗反应。重要的是，路易斯维尔大学的黑色素瘤多学科诊所和组织库拥有大量且不断增长的详细的去识别临床信息和来自I-IV期黑色素瘤患者的多个纵向血浆标本（bbb3000个血浆样本和目前219个切除的黑色素瘤转移），我们建议访问这些样本以测试这种新的诊断方法。应用DSC分析表征血浆蛋白质组，为疾病的检测和监测提供了一种全新的、互补的生物分析方法。DSC监测与生物分子热变性相关的热变化，产生组分，它们的数量和相互作用的独特特征。初步数据表明，使用DSC直接分析小体积血浆可产生对与健康状况相关的大量血浆蛋白的热力学性质差异敏感的剖面（或热图）。DSC热像图显示对疾病病理和治疗反应的敏感性，因此可以作为一种新的诊断方法具有相当大的实用性。本提案的目的是检查DSC热像图与标准PET/CT成像的诊断，早期发现复发和评估黑色素瘤的治疗效果。如果我们成功了，我们提出的研究有可能有助于早期临床评估，直接影响黑色素瘤患者的护理。我们提出了三个目标。目的1与PET/CT相比，探讨DSC热像图在黑色素瘤的检测和分期分化中的应用。目的2将确定纵向血浆样本DSC分析的诊断性能，以检测III期患者手术切除后疾病复发。在Aim 3中，我们将确定DSC在评估BRAF+ IV期黑色素瘤患者早期治疗反应中的效用。

DESCRIPTION (provided by applicant): Stage IV melanoma kills approximately 40,000 individuals per year globally. Early detection of new metastases is essential since up to three metastastic tumors can be resected for cure and patients with limited disease burden have improved clinical outcomes to immunotherapeutic agents such as ipilimumab (anti- CTLA4). As a result, full-body FDG-PET and CT imaging assessments are routinely conducted every three months for surveillance and every two months for response assessment. However, the utility of these scans is limited by both cost and the contribution of cumulative radiation exposure to secondary malignancies. The development of new non-invasive approaches for melanoma detection and frequent monitoring thus is expected to result in a marked reduction in melanoma-related deaths. The overarching goal of our research is the development of differential scanning calorimetry (DSC) analysis of blood plasma as a new, non- invasive diagnostic to enable more frequent monitoring and facilitate early detection of recurrences and early assessment of therapeutic response. Importantly, the University of Louisville's Melanoma Multi- Disciplinary Clinic and Tissue Repository has a large and growing collection of detailed de-identified clinical information and multiple longitudinal plasma specimens from stage I-IV melanoma patients (>3000 plasma samples and currently 219 resected melanoma metastases) which we propose to access in order to test this novel diagnostic approach. The application of DSC analysis to characterize the blood plasma proteome in our lab has provided an entirely new and complementary bioanalytical approach for the detection and monitoring of disease. DSC monitors heat changes associated with the thermal denaturation of biomolecules yielding a unique profile characteristic of the components, their amounts and interactions. Preliminary data indicate that direct analysis of small volumes of plasma using DSC yields profiles (or thermograms) that are sensitive to differences in the thermodynamic properties of abundant plasma proteins related to health status. DSC thermograms show sensitivity to disease pathology and therapeutic response and therefore could have considerable utility as a new diagnostic approach. The goals of this proposal are to examine the performance of DSC thermograms alongside standard PET/CT imaging for the diagnosis, the early detection of recurrence and the assessment of therapeutic efficacy in melanoma. If we are successful, the proposed research has the potential to contribute to earlier clinical assessment that can directly impact the care of melanoma patients. We propose three aims. Aim 1 addresses the utility of DSC thermograms for the detection and stage differentiation of melanoma compared with PET/CT. Aim 2 will determine the diagnostic performance of DSC analysis of longitudinal plasma samples to detect disease recurrence following surgical resection in stage III patients. In Aim 3, we will determine the utility of DSC for the assessment of early response to treatment in BRAF+ stage IV melanoma patients.