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: 8926098
• 负责人: Carolyn J. Anderson
• 金额: $ 4.99万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8926098
• 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; Health; 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; non-invasive imaging; optical imaging; outcome forecast; peptidomimetics; prevent; 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（由申请人提供）：约60%的头颈部鳞状细胞癌（SCCHN）患者发生区域淋巴结转移[1]，是疾病预后和结局的最重要指标。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，从而可以预防转移，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，以量化整合素（也称为极晚期抗原4或VLA-4）和CXC趋化因子受体4（CXCR 4）水平，这两者在头颈癌转移到淋巴结中起着假定的作用。肿瘤淋巴管生成是指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，TAMs）在原发性肿瘤的生长和转移中起重要作用，包括促进肿瘤血管生成、肿瘤边缘侵袭、肿瘤细胞向血流内浸润和肺定植。淋巴管内皮细胞和TAM都被发现表达高水平的整合素，本提案的目标之一是共同成像这两个途径。还发现CXCR 4/SDF-1信号通路在促进癌症转移中起重要作用。本提案中要解决的假设是，通过PET和光学成像确定的淋巴管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CXCR 4水平将与SCCHN原位小鼠模型中原发性肿瘤向淋巴结的转移相关。为了解决这一假设，我们将研究用于成像淋巴管生成和TAM的整合素靶向PET和光学试剂，以及用于成像原发性肿瘤中趋化因子水平的CXCR 4靶向试剂。SCCHN的两种原位小鼠模型，其中将高转移性（OSC-19）或非转移性（UM 22 B）SCCHN肿瘤细胞注射到口底。将对PET和光学成像数据进行量化，并将其与转移率和转移程度相关联。将获得免疫组织化学和流式细胞术数据，以验证来自切除肿瘤的整合素和CXCR 4水平。在2年资助期结束时，我们预计将有证据表明，通过SCCHN小鼠模型中的VLA-4靶向和CXCR 4表达，淋巴管生成和TAM成像，以及转移潜力与靶向成像剂摄取的相关性。最终，需要解决的全球问题是，原发性肿瘤的SCCHN患者是否表现出肿瘤淋巴管生成，高水平的TAM和/或高CXCR 4表达，将在其癌症扩散之前预测转移的风险，以便可以应用适当的干预措施。

项目成果

PET imaging of very late antigen-4 in melanoma: comparison of 68Ga- and 64Cu-labeled NODAGA and CB-TE1A1P-LLP2A conjugates.

• DOI: 10.2967/jnumed.114.144881
• 发表时间: 2014-11
• 期刊: Journal of nuclear medicine : official publication, Society of Nuclear Medicine
• 作者: Beaino W;Anderson CJ
• 通讯作者: Anderson CJ

Evaluation of (68)Ga- and (177)Lu-DOTA-PEG4-LLP2A for VLA-4-Targeted PET Imaging and Treatment of Metastatic Melanoma.

• DOI: 10.1021/mp5006917
• 发表时间: 2015-06-01
• 期刊: Molecular pharmaceutics
• 影响因子: 4.9
• 作者: Beaino W;Nedrow JR;Anderson CJ
• 通讯作者: Anderson CJ