Development of PET Imaging Probes for Chemokine Receptors for Head....

头部趋化因子受体 PET 成像探针的开发...

• 批准号: 7490244
• 负责人: HYUNSUK SHIM
• 金额: $ 12.91万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7490244
• 关键词: Affinity; Agonist; Aldehydes; Amines; Animal Model; Antibodies; Benign; Binding; Biodistribution; Biological Markers; Bone Marrow; CCL7 gene; CXCR4 Receptors; CXCR4 gene; Cancer Patient; Carcinoma; Cell Line; Cells; Clinic; Clinical; Development; Diagnostic; Discrimination; Distant Metastasis; Drug Delivery Systems; Drug Kinetics; Drug or chemical Tissue Distribution; Early Diagnosis; Epidermal Growth Factor Receptor; Fluorine; Gamma counter; Goals; Half-Life; Head; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Homing; In Vitro; Kinetics; Label; Lesion; Ligands; Literature; Liver; Lung; Malignant - descriptor; Malignant Neoplasms; Mediating; Metabolic Clearance Rate; Metastatic Neoplasm to the Lung; Methods; Modeling; Molecular Weight; Monitor; Necrosis; Neoplasm Metastasis; Nodal; Nonmetastatic; Operative Surgical Procedures; Outcome; Paraffin Embedding; Patients; Peptides; Pharmaceutical Preparations; Physical condensation; Play; Positron; Positron-Emission Tomography; Primary Neoplasm; Proteins; Quality of life; Radiation; Rate; Rattus; Reporting; Risk; Role; Running; Sampling; Screening for cancer; Sep-Pak C18; Signal Transduction; Specificity; Squamous cell carcinoma; Stromal Cell-Derived Factor 1; Surface; TN14003; Time; Toxic effect; Tracer; Translating; Xenograft procedure; base; bone; cancer stem cell; chemokine; chemokine receptor; design; drug discovery; imaging probe; improved; in vivo; lymph nodes; metastatic process; migration; mouse model; neoplastic cell; novel; outcome forecast; pre-clinical; programs; radioligand; receptor; response; size; small molecule; synthetic peptide; tool; tumor; uptake

This preclinical biomarker development study focuses on the chemokine receptors that mediate the migration of cancer stem cells to the lymph nodes, lungs, liver, and bones. Squamous cell carcinoma (SCC), a malignant tumor of epithelial origin, represents more than 90% of all Head and Neck cancers. While lymph node metastases are more common in SCCHN patients (~60%), approximately 20 to 25% of patients with SCCHN develop distant metastases, primarily in the lungs, liver, and bone. SCCHN patients without nodal and distant metastases are likely to have a more favorable prognosis than their counterparts. We established metastatic SCCHN cell lines from a poorly metastatic parental cell line by four rounds of in vivo selection using a lymph node metastatic xenograft mouse model. We observed that metastatic clones of SCCHN expressed high levels of CXCR4 and CCR7 chemokine receptors while non-metastatic parental clones established from the primary tumor of the same model did not. These results suggest that CXCR4 and CCR7 are required for the metastatic process. Our goal is to develop 18F-PET tracers to detect SCCHN metastases by using CXCR4 and CCR7 as biomarkers. The hypothesis is that CXCR4 and CCR7 are required for SCCHN metastasis; thus one can detect the tumor cells with high metastatic potential using antagonists that bind CXCR4 and CCR7 as imaging probes for PET. Specific aims are (1) Develop a 18Flabeled CXCR4 antagonist to detect metastatic tumor cells in vivo; (2) Develop small molecule-based radioligand to detect metastatic tumors cells; and (3) Develop a 18F-labeled CCR7 antagonist to detect metastatic tumor cells in vivo. We developed an efficient method to label and purify peptide-based antagonists (1.5 - 2 kDa) with fluorine-18, which is adequate for 18F-PET because the high signal to background ratio can be achieved within the time constraints due to the fast circulating/clearance rate. Furthermore, we have been running an active drug discovery program on developing anti-CXCR4 compounds. We have a wealth of potent novel small molecules suitable as PET probe with low nanomolar binding affinity to CXCR4. We will pursue to develop both peptide-based and low molecular weight radioligands for the PET probe to develop the most suitable radioligand to detect CXCR4-positive cells in vivo. The successful outcome of our study can be readily translatable into the clinic and will benefit cancer patients tremendously throught the prediction/early detection of cancer metastatsis. Moreover, we can apply the similar approach trageting other surface receptors that are frequently implicated in cancer. Thus, this same imaging probe can be utilized to develop/evaluate novel candidate small molecule drugs and their pharmacokinetics.

这项临床前生物标志物开发研究的重点是介导趋化因子受体 癌症干细胞迁移至淋巴结、肺、肝脏和骨骼。鳞状细胞癌（SCC）， 一种上皮来源的恶性肿瘤，占所有头颈癌的 90% 以上。而淋巴 淋巴结转移在 SCCHN 患者中更为常见 (~60%)，大约 20% 至 25% 的患者存在淋巴结转移 SCCHN 发生远处转移，主要发生在肺、肝和骨中。无淋巴结的 SCCHN 患者 远处转移可能比其对应部位有更好的预后。我们 通过四轮体内实验，从转移不良的亲本细胞系建立了转移性 SCCHN 细胞系 使用淋巴结转移异种移植小鼠模型进行选择。我们观察到转移性克隆 SCCHN 表达高水平的 CXCR4 和 CCR7 趋化因子受体，而非转移性亲本 从同一模型的原发性肿瘤建立的克隆则没有。这些结果表明 CXCR4 和CCR7是转移过程所必需的。我们的目标是开发 18F-PET 示踪剂来检测 使用 CXCR4 和 CCR7 作为生物标志物进行 SCCHN 转移。假设 CXCR4 和 CCR7 SCCHN 转移所需；因此，人们可以使用以下方法检测具有高转移潜力的肿瘤细胞： 结合 CXCR4 和 CCR7 的拮抗剂作为 PET 成像探针。具体目标是 (1) 开发 18Flabeled CXCR4拮抗剂检测体内转移性肿瘤细胞； (2) 发展小分子基础 放射性配体检测转移性肿瘤细胞； (3) 开发18F标记的CCR7拮抗剂来检测 体内转移的肿瘤细胞。我们开发了一种有效的方法来标记和纯化基于肽的 氟 18 拮抗剂 (1.5 - 2 kDa)，这对于 18F-PET 来说是足够的，因为 由于快速的循环/清除率，可以在时间限制内实现背景比。 此外，我们一直在开展一项积极的药物发现计划，以开发抗 CXCR4 化合物。我们拥有丰富的有效的新型小分子，适合作为低纳摩尔的 PET 探针 与 CXCR4 的结合亲和力。我们将致力于开发基于肽的和低分子量的 用于 PET 探针的放射性配体，以开发最合适的放射性配体来检测 CXCR4 阳性细胞 体内。我们研究的成功结果可以很容易地转化为临床，并将有益于癌症 患者极大地经历了癌症转移的预测/早期检测。此外，我们还可以申请 类似的方法针对经常与癌症有关的其他表面受体。因此，这个 相同的成像探针可用于开发/评估新型候选小分子药物及其 药代动力学。