This preclinical biomarker development study focuses on the chemokine receptors that mediate themigration 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 lymphnode metastases are more common in SCCHN patients (~60%), approximately 20 to 25% of patients withSCCHN develop distant metastases, primarily in the lungs, liver, and bone. SCCHN patients without nodaland distant metastases are likely to have a more favorable prognosis than their counterparts. Weestablished metastatic SCCHN cell lines from a poorly metastatic parental cell line by four rounds of in vivoselection using a lymph node metastatic xenograft mouse model. We observed that metastatic clones ofSCCHN expressed high levels of CXCR4 and CCR7 chemokine receptors while non-metastatic parentalclones established from the primary tumor of the same model did not. These results suggest that CXCR4and CCR7 are required for the metastatic process. Our goal is to develop 18F-PET tracers to detectSCCHN metastases by using CXCR4 and CCR7 as biomarkers. The hypothesis is that CXCR4 and CCR7are required for SCCHN metastasis; thus one can detect the tumor cells with high metastatic potential usingantagonists that bind CXCR4 and CCR7 as imaging probes for PET.
Specific aims are (1) Develop a 18FlabeledCXCR4 antagonist to detect metastatic tumor cells in vivo; (2) Develop small molecule-basedradioligand to detect metastatic tumors cells; and (3) Develop a 18F-labeled CCR7 antagonist to detectmetastatic tumor cells in vivo. We developed an efficient method to label and purify peptide-basedantagonists (1.5 - 2 kDa) with fluorine-18, which is adequate for 18F-PET because the high signal tobackground 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-CXCR4compounds. We have a wealth of potent novel small molecules suitable as PET probe with low nanomolarbinding affinity to CXCR4. We will pursue to develop both peptide-based and low molecular weightradioligands for the PET probe to develop the most suitable radioligand to detect CXCR4-positive cells invivo. The successful outcome of our study can be readily translatable into the clinic and will benefit cancerpatients tremendously throught the prediction/early detection of cancer metastatsis. Moreover, we can applythe similar approach trageting other surface receptors that are frequently implicated in cancer. Thus, thissame imaging probe can be utilized to develop/evaluate novel candidate small molecule drugs and theirpharmacokinetics.
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