Molecular Imaging directed Diagnosis and Interrogation of Human Soft Tissue....

研究部分3将集中于临床和新型小鼠模型中人类软组织肉瘤（STS）的分子成像指导诊断和询问。STS是一种异质性结缔组织肿瘤，约占成人恶性肿瘤的1%和儿科恶性肿瘤的15%。非侵入性分子成像已成为监测人类恶性肿瘤治疗反应的一种有效方式。我们最近的研究表明，这种方法在某些组织学亚型STS的治疗中是重要的。我们的长期目标是应用现有的成像方式和研究新的分子/代谢成像工具，在明确定义的STS患者通路病变的背景下指导和监测靶向治疗。我们最初的研究发现，在我们的小鼠模型和人类患者中，PTEN缺失和FDG摄取增加与良性神经纤维瘤（NF）向恶性周围神经鞘肿瘤（MPNST）的恶性转化相关，这为(i) PTEN/P13K/AKT通路在控制NF的良性向恶性转化中的重要作用以及（ii）使用FDG- pet成像非侵入性地推断该通路的状态提供了令人信服的证据。在Aim 1中，我们将使用FDG-PET成像来评估PTEN/PI3K/AKT的致癌途径状态，并在我们的基因工程小鼠模型、直接到宿主的异种移植模型和MPNST患者中监测对靶向联合治疗的反应。在Aim 2中，我们将重点研究那些恶性STS，如脂肪肉瘤，尽管临床分级高，但FDG摄取低（低糖酵解活性）。我们推断，这些低糖酵解表型的恶性肿瘤可能依赖于碳源而不是葡萄糖来持续增殖。我们将通过询问我们的脂肪肉瘤FDG-PET， SNP和mRNA阵列数据集对这些肿瘤进行全面分析。我们的目标是识别那些独立于FDG信号的恶性肿瘤信号。然后，我们将研究与这些不依赖fdg的恶性特征相关的其他上调代谢途径。理解这些

Research component 3 will focus on molecular imaging directed diagnosis and interrogation of human soft tissue sarcomas (STS) in the clinic and in new murine model. STS are a heterogeneous group of connective tissue tumors that comprise about 1 percent of aduit and 15 percent of pediatric malignancies. Non-invasive molecular imaging has become an effective modality to monitor therapeutic responses in human malignancies. Our recent studies have demonstrated this approach to be important in the management of certain histologic subtypes of STS. Our long-term goal is to apply existing imaging modalities and investigate novel molecular/metabolic imaging tools to direct and monitor targeted therapies in the context of cleariy defined pathway lesions in patients with STS. Our original finding that PTEN loss and increased FDG uptake correlate with the malignant transformation of benign neurofibromas (NF) to malignant peripheral nerve sheath tumors (MPNST) in both our mouse model and in human patients makes a compelling case for (i) the essential role of the PTEN/P13K/AKT pathway in controlling the benign to malignant transformation of NFs and (ii) the use of FDG-PET imaging to non-invasively infer the status of this pathway. In Aim 1 we will use FDG-PET imaging to assess the PTEN/PI3K/AKT oncogenic pathways status and monitor the response to targeted combination treatments in our genetically engineered mouse model, in a direct-to-host xenograft model and in patients with MPNST. In Aim 2 we will focus our investigation on those malignant STS, such as liposarcoma, which have low FDG uptake (low glycolytic activity) despite being clinically high grade. We reason that malignant tumors with these low glycolytic phenotypes may rely on carbon sources other than glucose for their continuous proliferation. We will conduct a comprehensive analysis of these tumors by interrogating our liposarcoma FDG-PET, SNP and mRNA array data sets. Our objective is to identify those signatures of malignancy that are independent of FDG signatures. We will then investigate other upregulated metabolic pathways associated with these FDG-independent malignant signatures. Understanding these pathways will enable us to design new strategies for their molecular imaging and targeted therapy.