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

这项临床前生物标记物开发研究的重点是趋化因子受体，它介导了 癌症干细胞向淋巴结、肺、肝脏和骨骼的迁移。鳞癌(SCC)， 一种起源于上皮源性的恶性肿瘤，占所有头颈部癌症的90%以上。而淋巴 淋巴结转移在SCCHN患者中更为常见(~60%)，约20%至25%的患者 SCCHN发生远处转移，主要发生在肺、肝和骨。无结节的SCCHN患者 而且远处转移的预后可能比相应的转移更好。我们 从低转移亲本细胞系体内四轮建立转移SCCHN细胞系 选用淋巴结转移性异种移植小鼠模型。我们观察到转移的克隆 SCCHN高水平表达CXCR4和CCR7趋化因子受体 从同一模型的原发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示踪剂来检测 以CXCR4和CCR7作为SCCHN转移的生物标志物。假设CXCR4和CCR7 是SCCHN转移所必需的；因此，人们可以使用 结合CXCR4和CCR7作为PET成像探针的拮抗剂。具体目标是(1)开发18F标签 CXCR4拮抗剂用于检测体内转移的肿瘤细胞；(2)开发基于小分子的 放射性配基用于检测转移的肿瘤细胞；以及(3)开发18F标记的CCR7拮抗剂用于检测 体内转移的肿瘤细胞。我们开发了一种有效的标记和纯化多肽的方法 拮抗剂(1.5-2 kDa)与氟-18，这是足够的18F-PET，因为高信号到 由于快速的循环/清除速率，可以在时间限制内实现本底比。 此外，我们一直在进行积极的药物发现计划，开发抗CXCR4 化合物。我们有丰富的有效的新的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多肽和低分子量的产品 应用放射性配基检测CXCR4阳性细胞的研究 活着。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 在癌症转移的预测/早期发现方面，患者发挥了巨大作用。此外，我们还可以申请 类似的方法是捕捉经常与癌症有关的其他表面受体。因此，这一点 可以使用相同的成像探针来开发/评价新的候选小分子药物及其 药物动力学。

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.