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

这项临床前生物标志物开发研究的重点是介导细胞凋亡的趋化因子受体。 癌症干细胞向淋巴结、肺、肝和骨的迁移。鳞状细胞癌（SCC）， 一种上皮起源的恶性肿瘤，占所有头颈部癌症的90%以上。虽然淋巴 淋巴结转移在SCCHN患者中更常见（约60%），约20 - 25%的SCCHN患者 SCCHN发生远处转移，主要在肺、肝和骨中。无淋巴结转移的SCCHN患者 并且远处转移可能比它们的对应物具有更有利的预后。我们 通过四轮体内实验从转移性差的亲本细胞系建立转移性SCCHN细胞系， 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， SCCHN表达高水平的CXCR 4和CCR 7趋化因子受体，而非转移性亲本 从相同模型的原发肿瘤建立的克隆则没有。这些结果表明，CXCR 4 和CCR 7是转移过程所必需的。我们的目标是开发18F-PET示踪剂， 使用CXCR 4和CCR 7作为生物标志物的SCCHN转移。假设CXCR 4和CCR 7 是SCCHN转移所必需的;因此，可以使用 结合CXCR 4和CCR 7的拮抗剂作为PET的成像探针。具体目标是：（1）开发一个18F标记的 CXCR 4拮抗剂检测体内转移性肿瘤细胞;（2）开发基于小分子的 放射性配体检测转移性肿瘤细胞;和（3）开发18F-标记的CCR 7拮抗剂，以检测 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肽基 拮抗剂（1.5 - 2 kDa）与氟-18，这是足够的18F-PET，因为高信号， 由于快速的循环/清除速率，可以在时间限制内实现背景比。 此外，我们一直在进行一项积极的药物发现计划，以开发抗CXCR 4 化合物.我们有丰富的有效的新型小分子适合作为PET探针，具有低纳摩尔浓度 与CXCR 4的结合亲和力。我们将致力于开发肽基和低分子量 PET探针的放射性配体，以开发最合适的放射性配体来检测CXCR 4阳性细胞， vivo.我们研究的成功结果可以很容易地转化为临床，并将有利于癌症 患者对癌症转移的预测/早期检测非常正确。此外，我们可以申请 类似的方法可以抑制其他经常与癌症有关的表面受体。因此， 相同的成像探针可用于开发/评估新的候选小分子药物及其组合物。 药代动力学

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.