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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：
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
项目类别：
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

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.

本临床前生物标志物开发研究的重点是介导的趋化因子受体