Gastroenteropancreatic neuroendocrine neoplasms (GEP NENs) are rare cancers consisting of neuroendocrine carcinomas (NECs) and neuroendocrine tumors (NETs), which have been increasing in incidence in recent years. Few cell lines and pre-clinical models exist for studying GEP NECs and NETs, limiting the ability to discover novel imaging and treatment modalities. To address this gap, we isolated tumor cells from cryopreserved patient GEP NECs and NETs and injected them into the flanks of immunocompromised mice to establish patient-derived xenograft (PDX) models. Two of six mice developed tumors (NEC913 and NEC1452). Over 80% of NEC913 and NEC1452 tumor cells stained positive for Ki67. NEC913 PDX tumors expressed neuroendocrine markers such as chromogranin A (CgA), synaptophysin (SYP), and somatostatin receptor-2 (SSTR2), whereas NEC1452 PDX tumors did not express SSTR2. Exome sequencing revealed loss of TP53 and RB1 in both NEC tumors. To demonstrate an application of these novel NEC PDX models for SSTR2-targeted peptide imaging, the NEC913 and NEC1452 cells were bilaterally injected into mice. Near infrared-labelled octreotide was administered and the fluorescent signal was specifically observed for the NEC913 SSTR2 positive tumors. These 2 GEP NEC PDX models serve as a valuable resource for GEP NEN therapy testing.
Dye design can influence the ability of fluorescently labeled imaging agents to generate tumor contrast and has become an area of significant interest in the field of fluorescence-guided surgery (FGS). Here, we show that the charge-balanced nearinfrared fluorescent (NIRF) dye FNIR-Tag enhances the imaging properties of a fluorescently labeled somatostatin analogue. In vitro studies showed that the optimized fluorescent conjugate MMC-(FNIR-Tag)-TOC bound primarily via somatostatin receptor subtype-2 (SSTR2), whereas its negatively charged counterpart with IRDye 800CW had higher off-target binding. NIRF imaging in cell line-and patient-derived xenograft models revealed markedly higher tumor contrast with MMC(FNIR-Tag)-TOC, which was attributed to increased tumor specificity. Ex vivo staining of surgical biospecimens from primary and metastatic tumors, as well as involved lymph nodes, demonstrated binding to human tumors. Finally, in an orthotopic tumor model, a simulated clinical workflow highlighted our unique ability to use standard preoperative nuclear imaging for selecting patients likely to benefit from SSTR2-targeted FGS. Our findings demonstrate the translational potential of MMC(FNIR-Tag)-TOC for intraoperative imaging and suggest broad utility for using FNIR-Tag in fluorescent probe development.
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