Development of a new class of radiopharmaceuticals for diagnosis and therapy of CXCR4-expressing malignancies based on the endogenous CXCR4 antagonist EPI-X4

C-X-C基序趋化因子受体4(CXCR4)在超过23种人类癌症中的病理性过表达使CXCR4成为肿瘤学中一个广谱的分子靶点。在核医学中，放射性标记分子可以专门针对这种细胞表面受体，并可以设计用于在同一分子内混合诊断和治疗特性(放射治疗)。最近，CXCR4的内源性拮抗剂和反向激动剂EPI-X4已经被申请者发现。EPI-X4是一种从人血清白蛋白中提取的16肽，可与CXCR4特异性结合，但不与其他G蛋白偶联受体(GPCRs)结合。几种合成的EPI-X4衍生物已经被开发出来，它们与CXCR4的亲和力增强，对血液中的蛋白质降解具有抵抗力，并具有较高的系统保留时间。因此，基于EPI-X4的放射治疗可能为CXCR4表达的恶性肿瘤患者提供新的成像测试和治疗选择。这项拟议的研究项目将是第一项旨在评估一类新的放射性药物的研究，该药物基于人体内自然存在的一种内源性多肽，与小分子相比，这种多肽可能具有较少的脱靶效应。

The pathological overexpression of the C-X-C motif chemokine receptor 4 (CXCR4) in more than 23 human cancers designate CXCR4 as a “wide spectrum” molecular target in oncology. In nuclear medicine, radiolabeled molecules can specifically target such cell surface receptors and can be designed for blending diagnostic and therapeutic properties within the same molecule (radio-theranostics). Recently, an endogenous antagonist and inverse agonist of CXCR4, termed EPI-X4, has been identified by the applicants. EPI-X4 is a 16-mer peptide derived from human serum albumin that specifically binds CXCR4 but no other G-protein coupled receptors (GPCRs). Several synthetic derivatives of EPI-X4 with increased affinity for CXCR4, resistance against proteolytic degradation in blood and high systemic retention times have been developed. Radio-theranostics based on EPI-X4 may thus offer new imaging tests and therapeutic options to patients suffering from CXCR4-expressing malignancies. The proposed research project would be the first study aiming to evaluate a new class of radiopharmaceuticals based on an endogenous peptide naturally present in the human body, which may have less off-target effects as compared to small molecules.