Establishment of Novel Neuroendocrine Carcinoma Patient-Derived Xenograft Models for Receptor Peptide-Targeted Therapy

Abstract

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.

Preclinical Models of Neuroendocrine Neoplasia

“…Compared to prostate cancers, where biobanks increasingly standardize protocols and collection procedures across regions, new NEN PDXs have been developed incrementally and by disparate methods [ 99 , 100 , 102 , 116 , 117 ]. Recently, 2 GEP-NEC PDX models have been described by Tran et al [ 97 ]. Beyond drug screening, some NEN PDXs have also been used to analyze circulating cancer cells [ 116 ].…”

High-Contrast Detection of Somatostatin Receptor Subtype-2 for Fluorescence-Guided Surgery

“…NOD scid γ mice (stock no: 005557; The Jackson Laboratory) were injected with 1 × 10 6 NEC913 (SSTR2+) and 7 × 10 5 NEC1452 (SSTR2-) NEC cells, as previously described, and studies were performed 4 weeks after implantation. 20 We used the percutaneous retro-orbital technique for intravenous injections and overdose of anesthesia followed by cervical dislocation as the method of euthanasia in terminal studies unless otherwise noted.…”

“…To further strengthen the rigor of our in vivo studies, a bilateral PDX tumor model was prepared using procedures approved by The University of Iowa’s Institutional Animal Care and Use Committee. NOD scid γ mice (stock no: 005557; The Jackson Laboratory) were injected with 1 × 10 6 NEC913 (SSTR2+) and 7 × 10 5 NEC1452 (SSTR2-) NEC cells, as previously described, and studies were performed 4 weeks after implantation . We used the percutaneous retro-orbital technique for intravenous injections and overdose of anesthesia followed by cervical dislocation as the method of euthanasia in terminal studies unless otherwise noted.…”

Establishment and validation of a clinicopathological prognosis model of gastroenteropancreatic neuroendocrine carcinomas

“…Therefore, the incidence of GEP-NECs has increased gradually in recent years (3)(4)(5). The incidence of NECs is less well defined due to changes in WHO classification over the past 10 years (6), but epidemiological studies estimate the rate to be approximately 0.4 per 100,000 person-years (5,7). In the United States, a total of 6,291 cases with GEP-NECs were diagnosed between 1973 and 2012 (8).…”