以甘氨酸脱羧酶为靶点的癌症早期诊断分子探针的研究

Non-invasive detection of cancer stem cells (CSC) is of great importance for cancer treatment, nevertheless is still a long-standing challenge in clinics. PET is a cutting-edge imaging technique that produces a 3-D image of functional processes in the body, and can distinguish diseased region from health tissue with great sensitivity. The most broadly used PET tracer is 18F-2-fluorodeoxyglucose (FDG). It is now the gold standard for PET neuroimaging and cancer patient management. However, [18F]FDG is not able to detect CSC as glucose metabolism is inactive in CSC. To discover a CSC specific PET tracer, here we describe a new glycine mimics—boron derived glycine (B-Gly), that is designed to serve as a specific imaging probe for Glycine Decarboxylase (GLDC). GLDC is recently reported as a specific marker for CSC. It is required for CSC growth and plays an essential role of promoting cellular transformation and tumorigenesis. GLDC catalyzes a chemical reaction, of which the two substrates are glycine and H-protein-lipoyllysine, whereas its two products are H-protein-S-aminomethyldihydro lipoyllysine and CO2. The structure of B-Gly is identical to that of glycine, except for a replacement of the carboxylate with trifluoroborate, which is an isostereo of carboxylate. According to our hypothesis, B-Gly can participate the decarboxylation progress but would not finish the complete reaction. Consequently, 18F-labelled B-Gly is metabolically trapped within GLDC and therefore highlight GLDC by using the radioactive signal from 18F isotope. In our previous study, B-Gly exhibits strong stability under both in vitro and in vivo conditions. The cellular uptake of B-Gly follows the similar pathway as Gly, suggesting that B-Gly holds great promise for the development of new imaging probe for targeting GLDC under in vivo conditions. In this proposal, a novel PET imaging probe is expected to be discovered for CSC and guiding corresponding treatments.

癌症的早期诊断是癌症治疗的关键，也是临床中面临的一个重大难题。本课题拟借助于放射性分子成像技术，以三氟化硼和羧酸根的生物相似性为基础，发展针对肿瘤干细胞（CSC）的放射性分子探针。作为CSC的特异性靶点，甘氨酸脱羧酶（GLDC）在CSC上有着特异性的高表达。为了实现对GLDC的特异性识别，我们将甘氨酸中的羧基替换为三氟化硼，得到的硼甘氨酸（B-Gly）与甘氨酸（Gly）具有相似的化学结构，其可以做为GLDC的底物进入脱羧过程。本项目将通过建立GLDC高表达的细胞株以及活体动物成像实验，研究B-Gly与Gly的生物相似性，并通过放射性标记在活体上验证B-Gly的成像能力及其组织摄取与GLDC表达的定量关系。本课题将证实我们提出的“18F标记的B-Gly可特异性地识别CSC中的GLDC，并可通过放射性成像对CSC完成特异性识别”的假说, 为CSC的活体侦测以及癌症的早期诊断提供新思路。