Imaging Tumor Associated Macrophages in Bone Sarcomas

 描述(申请人提供)：患有恶性骨肉瘤和转移性疾病的儿童患者的总体五年存活率仅为30%。迫切需要新的预后生物标志物，它们可以作为新的系统治疗的靶点，并帮助改善这些患者的预后。肿瘤相关巨噬细胞()是新近发现的与肿瘤进展和恶性肉瘤患者预后不良相关的新的生物标志物。针对的新药目前正在开发中，并开始进入临床。为了对可能从这些新的调节疗法中受益的患者进行分层并监测治疗反应，重要的是确定严重浸润性肿瘤的患者。为了解决这一未得到满足的临床需求，我们建议开发一种新的、可立即应用于临床的分子成像测试，用于选择性检测和定量儿童骨肉瘤中的TAMS。这项新的成像测试依赖于标签外使用补铁阿魏酸醇，这是一种FDA批准的氧化铁纳米化合物，由吞噬。由于阿魏酸甘油酯纳米粒可以通过磁共振成像(MRI)检测到，我们假设阿魏酸甘油酯增强的MRI可以作为TAMS在骨肉瘤中的直接临床应用的成像生物标记物。据我们所知，这是首次尝试在患者体内使用FDA批准的纳米颗粒来可视化TAMS。在两个步骤的方法中，我们将首先在小鼠模型中调查拟议的阿魏酸甘油成像测试是否能够检测到对新的免疫调节癌症疗法的反应。随后，我们将通过将阿魏酸肿瘤的MRI增强与组织病理学的数量和分布相关联，为儿童骨肉瘤患者提供概念上的证据。这种动物模型和患者研究的结合将为联合临床成像研究建立初步数据，这是美国国家癌症研究所的一项新的精确医学倡议。对于临床医生来说，开发成像测试将是一项重大突破，因为它是一种新的风险分层手段，也是跟踪癌症免疫治疗试验治疗反应的黄金标准成像测试，包括计划于2016年在斯坦福大学进行的首例人抗CD47免疫疗法试验。

 DESCRIPTION (provided by applicant): The overall five-year survival of pediatric patients with malignant bone sarcomas and metastatic disease is only 30%. There is an urgent need for new prognostic biomarkers, which could serve as targets for new systemic therapies and help improve outcomes for these patients. Tumor-associated macrophages (TAM) have been recently identified as novel biomarkers, which are associated with tumor progression and poor prognosis in patients with malignant sarcomas. New therapeutic drugs that target TAM are currently being developed and are starting to enter the clinic. To stratify patients who might benefit from these novel TAM- modulating therapies and to monitor treatment responses, it is important to identify patients whose tumors are heavily infiltrated with TAM. We propose to address this unmet clinical need by developing a novel and immediately clinically applicable molecular imaging test for selective detection and quantification of TAMs in pediatric bone sarcomas. This new imaging test relies on off-label use of the iron supplement ferumoxytol, an FDA-approved iron oxide nanoparticle compound, which is phagocytosed by TAM. Since ferumoxytol nanoparticles can be detected with magnetic resonance imaging (MRI), we hypothesize that ferumoxytol- enhanced MRI can be used as an immediately clinically applicable imaging biomarker for TAMs in bone sarcomas. To the best of our knowledge, this is the first attempt to visualize TAMs with FDA-approved nanoparticles in patients. In a two-step approach, we will first investigate whether the proposed ferumoxytol TAM imaging test can detect responses to new immune-modulating cancer therapies in a mouse model. Subsequently, we will provide proof of concept in pediatric patients with bone sarcomas, by correlating ferumoxytol tumor MRI enhancement with histopathological TAM quantities and distribution. This combination of studies in animal models and patients will establish preliminary data for co-clinical imaging research, a new precision medicine initiative of the National Cancer Institute. Developing a TAM imaging test would represent a significant breakthrough for clinicians as a new means for risk stratification and as a gold-standard imaging test for tracking treatment response in cancer immunotherapy trials, including a planned first-in-man anti-CD47 immunotherapy trial at Stanford University in 2016.