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...

基本信息

批准号：
8135467
负责人：
HYUNSUK SHIM
金额：
$ 23.65万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8135467
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 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 small molecule synthetic peptide tool tumor uptake

项目摘要

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发展研究的重点是介导的趋化因子受体癌干细胞向淋巴结，肺，肝脏和骨骼的迁移。鳞状细胞癌（SCC），上皮起源的恶性肿瘤代表所有头颈部和颈部癌症的90％以上。而淋巴 SCCHN患者（约60％），淋巴结转移更为常见，约有20至25％ SCCHN主要在肺，肝脏和骨骼中发展遥远的转移。没有淋巴结的SCCHN患者远处转移可能比其对应物具有更有利的预后。我们从转移性不良的父母细胞系中建立的转移性SCCHN细胞系，体内四轮使用淋巴结转移性异种移植小鼠模型进行选择。我们观察到那个转移克隆 SCCHN表示高水平的CXCR4和CCR7趋化因子受体，而非转移性父母从同一模型的原发性肿瘤建立的克隆没有。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示踪剂以检测通过使用CXCR4和CCR7作为生物标志物，SCCHN转移酶。假设是CXCR4和CCR7 SCCHN转移需要；因此，可以使用高转移电位检测肿瘤细胞将CXCR4和CCR7作为PET的成像探针结合的拮抗剂。具体目的是（1）开发一个18百莉 CXCR4拮抗剂在体内检测转移性肿瘤细胞；（2）发展基于小分子放射性物体检测转移性肿瘤细胞；（3）开发一个18F标记的CCR7拮抗剂来检测体内转移性肿瘤细胞。我们开发了一种有效的方法来标记和纯化基于肽的方法与氟-18的拮抗剂（1.5-2 kDa），足以适合18F-PET，因为高信号到由于快速循环/清除率，可以在时间限制内实现背景比率。此外，我们一直在开展有关开发抗CXCR4的活跃药物发现计划化合物。我们有大量有效的新颖的小分子，适合用低纳摩尔的PET探针与CXCR4的结合亲和力。我们将追求开发基于肽的和低分子量 PET探测器开发最合适的放射性物体以检测CXCR4阳性细胞中的放射性物体体内。我们研究的成功结果很容易被翻译成诊所，并将受益患者在癌症转移的预测/早期检测过程中巨大的患者。而且，我们可以申请类似的方法是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。