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

通过靶向 VLA-4 和 CXCR4 对 SCCHN 转移潜能进行分子成像

• 批准号: 8593344
• 负责人: Carolyn J. Anderson
• 金额: $ 19.92万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-12 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8593344
• 关键词: Address; Adhesions; Adverse effects; Affinity; Antibodies; B-Lymphocytes; Binding; Biological Markers; Blood; CXC Chemokines; CXCL12 gene; CXCR4 gene; Cell Culture Techniques; Cells; Data; Disease; Distant; Distant Metastasis; Early Intervention; Event; Fibronectins; Flow Cytometry; Functional disorder; Funding; Goals; Head and Neck Cancer; Head and Neck Neoplasms; Head and Neck Squamous Cell Carcinoma; Human; Image; Immunohistochemistry; Integrin Binding; Integrin alpha4beta1; Integrins; Intervention; Leukocytes; Ligands; Lip structure; Lung; Lymphangiogenesis; Lymphatic Endothelial Cells; Lymphatic Vessel Tumors; Lymphatic vessel; Malignant Neoplasms; Modeling; Mus; Neck Dissection; Neoplasm Metastasis; Nodal; Operative Surgical Procedures; Optics; Organ; Outcome; Pain; Paresis; Pathway interactions; Patients; Play; Positron-Emission Tomography; Primary Neoplasm; Procedures; Quality of life; Radiolabeled; Reporting; Research; Risk; Role; Shoulder; Signal Pathway; Site; Squamous cell carcinoma; Staging; Stream; Stromal Cell-Derived Factor 1; Sublingual Region; T-Lymphocyte; Time; Tumor Angiogenesis; Tumor Cell Invasion; base; chemokine; chemokine receptor; cyanine dye 5; imaging modality; improved; lymph nodes; macrophage; malignant breast neoplasm; migration; molecular imaging; mouse model; neoplastic cell; new growth; optical imaging; outcome forecast; peptidomimetics; prevent; public health relevance; radiotracer; tumor; tumor growth; uptake

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.

描述（申请人提供）：约 60% 的头颈鳞状细胞癌 (SCCHN) 患者发生区域淋巴结转移[1]，这是疾病预后和结果的最重要指标。需要一种策略来识别癌症可能发生转移的患者，这将允许早期干预措施预防转移，从而提高 SCCHN 患者的生存率和生活质量。该提案的目标是开发 PET 和光学成像剂来量化整合素（也称为极晚期抗原 4 或 VLA-4）和 CXC 趋化因子受体 4 (CXCR4) 水平，这两者在肿瘤转移中都发挥着假定的作用。头颈癌转移至淋巴结。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相关。肿瘤相关巨噬细胞（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、肿瘤细胞内渗入血流和肺部定植。淋巴内皮细胞和 TAM 均被发现表达高水平的整合素，该提案的目标之一是对这两条通路进行整体成像。 CXCR4/SDF-1信号通路也被发现在促进癌症转移中发挥重要作用。本提案要解决的假设是，通过 PET 和光学成像测定，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原发性 SCCHN 肿瘤中的 CXCR4 水平，将与原发性肿瘤向肿瘤的转移相关。 SCCHN 原位小鼠模型中的淋巴结。为了解决这一假设，我们将研究用于对淋巴管生成和 TAM 进行共同成像的整合素靶向 PET 和光学试剂，以及用于对原发性肿瘤中趋化因子水平进行成像的 CXCR4 靶向试剂。 SCCHN 的两种原位小鼠模型，其中高度转移性 (OSC-19) 或非转移性 (UM22B) SCCHN 肿瘤细胞被注射到口底。 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 2 年资助期结束时，我们预计将有证据表明 SCCHN 小鼠模型中通过 VLA-4 靶向和 CXCR4 表达对淋巴管生成和 TAM 进行成像，以及转移潜力与靶向成像剂摄取的相关性。最终，要解决的全球问题是，具有肿瘤淋巴管生成、高水平 TAM 和/或高 CXCR4 表达的原发性肿瘤的 SCCHN 患者是否能够在癌症扩散之前预测转移风险，以便采取适当的干预措施。