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

描述（由申请人提供）：全球每年约有40，000人死于IV期黑素瘤。新转移灶的早期检测是必要的，因为可以切除多达三个恶性肿瘤以治愈，并且具有有限疾病负担的患者已经改善了免疫抑制剂如易普利姆玛（抗CTLA 4）的临床结果。因此，全身FDG-PET和CT成像评估通常每三个月进行一次监测，每两个月进行一次反应评估。然而，这些扫描的效用受到成本和累积辐射暴露对继发性恶性肿瘤的贡献的限制。因此，开发新的非侵入性黑色素瘤检测方法和频繁监测有望显著减少与黑色素瘤相关的死亡。我们研究的首要目标是开发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，并促进复发的早期检测和治疗反应的早期评估。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（Melanoma Multi-Disciplinary Clinic and Tissue Repository）具有大量且不断增长的来自I-IV期黑色素瘤患者的详细的去识别临床信息和多个纵向血浆样本（>3000个血浆样本和目前219个切除的黑色素瘤转移）的集合，我们提议访问这些集合以测试这种新的诊断方法。本实验室应用差示扫描量热分析技术对血浆蛋白质组进行表征，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监测与生物分子的热变性相关的热变化，产生组分、其量和相互作用的独特特征。初步数据表明，使用DSC直接分析小体积的血浆产生对与健康状况相关的丰富血浆蛋白质的热力学性质的差异敏感的曲线（或热谱图）。DSC热谱图显示对疾病病理和治疗反应的敏感性，因此作为一种新的诊断方法可能具有相当大的实用性。该提案的目标是检查DSC热谱图与标准PET/CT成像的性能，用于诊断，早期检测复发和评估黑色素瘤的治疗效果。如果我们成功了，拟议的研究有可能有助于早期的临床评估，直接影响黑色素瘤患者的护理。我们提出三个目标。目的1解决了与PET/CT相比，DSC热谱图在黑色素瘤检测和分期方面的实用性。目的2将确定纵向血浆样本的DSC分析的诊断性能，以检测III期患者手术切除后的疾病复发。在目标3中，我们将确定DSC用于评估BRAF+ IV期黑色素瘤患者对治疗的早期反应的效用。

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.