Plasma-based marker identification

NCI方案：9825 "奥拉帕尼和西地尼布治疗复发性卵巢癌的II期研究" 目前还没有已知的生物标志物可以预测对西地尼布加奥拉帕尼组合的反应。为了鉴定抗血管生成抑制的血液标志物，将检测基于杜克多重ELISA的血浆血管组检测试剂盒。该组由许多血管生成生物标志物组成（表1），包括Ang-2、基质细胞衍生因子（SDF）-1、VEGF-D、骨桥蛋白（OPN）和白细胞介素（IL）-6。为了开发最佳阵列，杜克团队利用了三种多重蛋白质阵列系统。许多分析物之前已在Aushon Biosystems生产的CiraScan平台上进行了验证。将采用的其他多重系统包括Meso Scale Discovery（MSD）和ProteinSimple平台。 ProteinSimple平台使用微毛细管流动池，与传统ELISA技术相比，可提高灵敏度和重现性。 开发和优化适当设计的面板，用于评价关键的血管生成和炎症标志物。 这种"Angiome"多重阵列最近已被NCI生物标志物审查委员会（BRC）批准作为综合生物标志物，用于西地尼布和奥拉帕尼在铂敏感性和铂耐药卵巢癌中的两项III期研究。 我们与NCI密切合作，开发了我们的验证方法，建立了蛋白质多重阵列分析的关键分析特征。Angiome多重阵列经过严格的评估，以确保数据质量。最近，该方法被用于确定贝伐单抗获益的几个强有力的候选预测因子，包括VEGF-D和IL-6。目前正在卵巢癌中进行研究，以调查该血浆血管组组在指导贝伐单抗和西地尼布/奥拉帕尼组合治疗中的效用。 这种方法在技术上是稳健的，并且易于适应临床实践。由于这些数据将来自患者，即使是初步的数据也可能显着提高我们对癌症患者中血管生成和肿瘤生长因子如何调节的理解。有希望的发现可以在未来的临床研究和临床前模型中进行后续研究。由于杜克血管组实验室是联盟内多重ELISA分析的核心实验室，因此可以将当前的卵巢癌谱与其他III期研究中观察到的谱进行比较，有助于优化未来的谱方法，并提供有临床意义的伴随诊断所需的疾病特异性背景。鉴于这一先前工作的结果和其他人的工作，我们预期能够识别和验证或反驳抗血管生成剂特异性的候选有益标志物。

NCI Protocol: 9825 “A Phase 2 Study of Olaparib and Cediranib for the Treatment of Recurrent Ovarian Cancer” Currently there is no known biomarker that might predict for a response to the cediranib plus olaparib combination. To identify blood-based markers of anti-angiogenic inhibition, the Duke multiplex ELISA-based plasma angiome panel will be tested. This panel consists of a number of angiogenic biomarkers (Table 1), including Ang-2, stromal cell-derived factor (SDF)-1, VEGF-D, osteopontin (OPN), and interleukin (IL)-6. In order to develop the most optimal arrays, the Duke team leverages three multiplex protein array systems. Many analytes have been previously validated on the CiraScan platform, produced by Aushon Biosystems. Additional multiplex systems that will be employed include the Meso Scale Discovery (MSD) and ProteinSimple platforms. The ProteinSimple platform uses microcapillary flow cells for improved sensitivity and reproducibility versus traditional ELISA techniques. Development and optimization of an appropriately designed panel for the evaluation key angiogenic and inflammatory markers. This “Angiome” multiplex array has recently been approved by the NCI Biomarker Review Committee (BRC) as an integrated biomarker for use in two Phase III studies of cediranib and olaparib in both platinum-sensitive and platinum-resistant ovarian cancer. We worked closely with the NCI in developing our validation approach, establishing the key analytic features for protein multiplex array analyses. The Angiome multiplex array has gone through a rigorous evaluation to ensure data quality. Recently, the approach was used to identify several strong candidate predictors of benefit from bevacizumab, including VEGF-D and IL-6. Studies are underway in ovarian cancer to investigate the utility of this plasma angiome panel in directing treatment with bevacizumab and with the cediranib/olaparib combination. This approach is technically robust and readily adaptable to clinical practice. Because this data will be derived from patients, even preliminary data may significantly improve our understanding of how angiogenesis and tumor growth factors are regulated in cancer patients. Promising findings can be followed up in future clinical studies and in preclinical models. Because the Duke angiome lab serves as the core lab for multiplex ELISA analyses within the Alliance, the current ovarian cancer profiling can be compared to the profiles seen in other phase III studies, helping to optimize future profiling approaches and provide the disease specific context needed for clinically meaningful companion diagnostics. Given the results of this prior work and the work of others, we anticipate being able to identify and validate or refute candidate markers of benefit that are specific for anti-angiogenic agents.