Molecular Imaging of Metastatic Potential in SCCHN by Targeting VLA-4 and CXCR4

描述（申请人提供）：约60%的头颈部鳞状细胞癌（SCCHN）患者发生区域淋巴结转移，是疾病预后和转归的最重要指标。需要一种策略来识别癌症可能转移的患者，这将允许早期干预，可能防止转移，从而提高SCCHN患者的生存率和生活质量。本提案的目标是开发PET和光学显像剂来量化整合素（也称为非常晚期抗原4或vla4）和CXC趋化因子受体4 （CXCR4）的水平，这两种物质在头颈癌转移到淋巴结中都起着被认为的作用。肿瘤淋巴管生成是肿瘤周围新淋巴管的生长，这与淋巴结转移的形成有关。肿瘤相关巨噬细胞（Tumor associated macrophages, tam）已被证明在原发性肿瘤生长和转移中发挥重要作用，包括促进肿瘤血管生成、肿瘤边缘侵袭、肿瘤细胞内渗进入血流和肺部定植。淋巴内皮细胞和tam都被发现表达高水平的整合素，本提案的目标之一是对这两种途径进行综合成像。CXCR4/SDF-1信号通路也被发现在促进癌症转移中起重要作用。本研究提出的假设是，通过PET和光学成像检测，原发性SCCHN肿瘤中淋巴内皮细胞和肿瘤相关巨噬细胞（tam）中的整合素水平以及CXCR4水平与原位小鼠SCCHN模型中原发性肿瘤向淋巴结的转移有关。为了验证这一假设，我们将研究整合素靶向PET和光学试剂用于淋巴管生成和tam成像，以及CXCR4靶向试剂用于原发性肿瘤趋化因子水平成像。两种原位SCCHN小鼠模型，将高度转移（OSC-19）或非转移（UM22B） SCCHN肿瘤细胞注射到口腔底。PET和光学成像数据将被量化并与转移率和程度相关。将获得免疫组织化学和流式细胞术数据来验证切除肿瘤中整合素和CXCR4的水平。在为期2年的资助期结束时，我们预计将有证据表明，在SCCHN小鼠模型中，通过VLA-4靶向和CXCR4表达来成像淋巴管生成和tam，以及转移潜力与靶向显像剂的摄入之间的相关性。最终，需要解决的全球性问题是，原发性肿瘤表现出肿瘤淋巴管生成、高水平tam和/或高水平CXCR4表达的SCCHN患者是否可以在癌症扩散之前预测转移风险，从而应用适当的干预措施。

DESCRIPTION (provided by applicant): Metastasis to the regional lymph nodes occurs in about 60% of patients with squamous cell carcinoma of the head and neck (SCCHN) [1] and is the most important indicator of disease prognosis and outcome. A strategy is needed to identify patients whose cancers are likely to be metastatic, which will allow for early interventions that may prevent metastasis and thereby improve survival and quality of life in SCCHN patients. The goal of this proposal is to develop PET and optical imaging agents to quantify integrin (also called very late antigen 4, or VLA-4) and CXC chemokine receptor 4 (CXCR4) levels, both of which play a putative role in the metastasis of head and neck cancer to lymph nodes. Tumor lymphangiogenesis is the growth of new lymphatic vessels within the periphery of the tumor, and this has been correlated to the formation of lymph node metastases. Tumor associated macrophages (TAMs) have been shown to play important roles in primary tumor growth and metastasis, including promoting tumor angiogenesis, tumor invasion at the edge, tumor cell intravasation into the blood stream and lung colonization. Lymphatic endothelial cells and TAMs are both found to express high levels of integrin, and one of the goals of this proposal is to image these two pathways collectively. The CXCR4/SDF-1 signaling pathway has also been found to serve an important role in the promotion of cancer metastasis. The hypothesis to be addressed in this proposal is that the levels of integrin in lymphatic endothelial cells and tumor associated macrophages (TAMs), and CXCR4 in primary SCCHN tumors as determined by PET and optical imaging, will correlate with metastasis of the primary tumor to the lymph nodes in orthotopic mouse models of SCCHN. To address the hypothesis we will investigate integrin -targeting PET and optical agents for imaging lymphangiogenesis and TAMs collectively, and CXCR4- targeting agents for imaging chemokine levels in primary tumors. Two orthotopic mouse models of SCCHN, where either highly metastatic (OSC-19) or non-metastatic (UM22B) SCCHN tumor cells are injected into the floor of the mouth. PET and optical Imaging data will be quantified and correlated with rates and extent of metastasis. Immunohistochemistry and flow cytometry data will be obtained to validate levels of integrin and CXCR4 from excised tumors. At the end of the 2-year funding period, we anticipate that there will be evidence for the imaging of lymphangiogenesis and TAMs through VLA-4 targeting and CXCR4 expression in mouse models of SCCHN and correlation of metastatic potential with uptake of the targeted imaging agents. Ultimately, the global question to be addressed is whether SCCHN patients with primary tumors demonstrating tumor lymphangiogenesis, high levels of TAMs and/or high CXCR4 expression will predict the risk for metastasis before their cancer spreads, so that the appropriate interventions can be applied.