PO.CL01.23 · 临床研究
利用现有诊疗探针检测循环肿瘤细胞（CTCs）作为神经内分泌肿瘤（NETs）的新一代液体活检
Detection of circulating tumor cells (CTCs) as a next-generation liquid biopsy for neuroendocrine tumors (NETs) by taking advantage of existing theranostic probes
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摘要 Abstract
中文摘要
当神经内分泌细胞发生癌变时，由此产生的神经内分泌肿瘤（NETs）可能难以检测。NETs通常无症状，因为它们往往导致激素失衡，而这些失衡与其他疾病相关。在生物标志物方面，NETs常过表达生长抑素受体2（SSTR2）。该生物标志物是检测和治疗NETs的主要方法，一种名为DOTATATE的特定分子被用于临床PET扫描和治疗，以在NET患者中检测和对抗这种癌症。DOTATATE化合物由两个活性成分构成。DOTA成分是一种金属螯合剂，携带被PET扫描检测的成分。TATE成分是一种经修饰的奥曲肽酸（octreotate）化合物，可与生长抑素受体2（SSTR2）结合。在此，我们提供TATE-Cy5探针，它利用DOTATATE的临床用途来进行血液检测。与DOTATATE类似，TATE-Cy5同样含有酪氨酸-3-奥曲肽酸（tyrosine-3-octreotate），意味着它能够以同等有效性与SSTRs结合。然而，TATE-Cy5并非采用DOTA螯合剂，而是带有荧光Cy5探针，可用于检测NETs的存在，因为我们假设能够在患者血液样本中检测到循环肿瘤细胞（CTCs）。我们预测，在患者全血样本中，根据疾病严重程度会有大量结合TATE-Cy5探针的CTCs。结果显示，TATE-Cy5可与过表达SSTR2的细胞系结合。进入临床样本阶段，我们还在NET患者的全血样本中观察到结合TATE-Cy5的CTCs的存在。我们进一步根据共表达生物标志物的组合对CTCs进行了亚分类，包括SSTR2阳性的CTCs，以及SSTR2和EpCAM双阳性的肿瘤细胞。通过进一步检测，我们将能够使用TATE-Cy5来随时间监测患者的治疗反应。总之，我们开发了一种新型且癌症特异性的CTC液体活检方法，它利用了现有的成像探针DOTATATE。该技术具有重要的临床意义，因为它可作为现有和新兴疗法的伴随液体活检手段。
查看英文原文 English abstract
When neuroendocrine cells become cancerous, the resulting Neuroendocrine Tumours (NETs) can be challenging to detect. NETs are often asymptomatic, because they often lead to hormonal imbalances, which are associated with other diseases. In terms of biomarkers, NETs often overexpress Somatostatin Receptor 2 (SSTR2). This biomarker is the primary method of detecting and treating NETs and a specific molecule called DOTATATE is used for clinical PET scans and therapies to detect and combat this cancer in NET patients. DOTATATE compounds consist of two active components. The DOTA component is a metal chelator that carries the component detected by PET scan. The TATE component is a modified octreotate compound which binds to the Somatostatin Receptor 2 (SSTR2).Here, we offer the TATE-Cy5 probe, which takes advantage of the clinical use of DOTATATE for use in a blood test. Similar to DOTATATE, TATE-Cy5 also contains tyrosine-3-octreotate, meaning that it can to bind to SSTRs with equal effectiveness. However, instead of the DOTA chelator, TATE-Cy5 has a fluorescent Cy5 probe, which can be used to detect the presence of NETs because we hypothesize we can detect circulating tumor cells (CTCs) in patient blood samples. We predict that there are high numbers of CTCs that bind the TATE-Cy5 probe in patient whole blood samples according to disease severity.Results show that TATE-Cy5 binds to cell lines overexpressing SSTR2. Moving onto clinical samples, we also observe the presence of CTCs that bind TATE-Cy5 in whole blood samples from NET patients. We further subclassified CTCs as based on a combination of co-expressing biomarkers, CTCS that are positive for SSTR2, and tumours positive for both SSTR2 and EpCAM. With further testing, we will be able to use TATE-Cy5 to monitor patient treatment response over time.In summary, we have developed a novel and cancer specific CTC liquid biopsy that takes advantage of existing imaging probes in the form of DOTATATE. This technology has significant clinical implications because it can be used as a companion liquid biopsy for existing and emerging therapies.
利益披露 Disclosure
M. Greenberg, None..
E. Silva Nigenda, None..
J. Hallet, None..
S. Singh, None..
J. Trant, None..
H. Leong, None.