An Orthotopic Model of Pancreatic Somatostatin Receptor (SSTR)-Positive Tumors Allows Bimodal Imaging Studies Using 3T MRI and Animal PET-Based Molecular Imaging of SSTR Expression

Abstract

Somatostatin receptor (SSTR) scintigraphy is currently used as one standard imaging modality in neuroendocrine tumors (NETs). However, future optimization of NET imaging may be achieved with positron emission tomography based methods utilizing more sensitive and specific tracers in combination with computed tomography or magnetic resonance imaging. Here we established an orthotopic mouse model that reflects relevant aspects of human pancreatic NETs such as SSTR expression, dense vascularization and metastatic disease. This model was then utilized to test the feasibility of combined magnetic resonance imaging and animal positron emission tomography. Orthotopic implantation of amphicrine, SSTR-positive pancreatic AR42J cells resulted in rapidly growing tumors, with concomitant metastatic spread into abdominal lymph nodes and peritoneal cavity. Primary tumors as well as their metastases expressed the neuroendocrine markers chromogranin A and synaptophysin. For imaging experiments, the SSTR ligands ⁶⁸Ga-DOTATOC or ⁶⁸Ga-DOTANOC were injected intravenously, and animals were subsequently examined in an animal positron emission tomography scanner and a clinical 3T (tesla) magnetic resonance imager. All animals showed radionuclide accumulation in the primary tumor. Definite anatomical correlation was achieved using digital image fusion of the positron emission tomography and magnetic resonance imaging data. ⁶⁸Ga-DOTANOC strongly accumulated in the tumor tissue (mean 6.6-fold vs. control tissues) when compared to ⁶⁸Ga-DOTATOC, which showed a higher renal clearance. In good agreement with the biodistribution data, the kidney-to-tumor ratio was higher for ⁶⁸Ga-DOTATOC (2.43-fold vs. 1.75-fold). Consequently, ⁶⁸Ga-DOTANOC achieved better signal enhancement in the primary tumor and allowed for detection of metastatic lesions. In summary, we established a novel orthotopic pancreatic SSTR-positive tumor model and used this model to provide proof of principle for the diagnostic combination of SSTR-based molecular imaging and magnetic resonance imaging. Specifically, the animal model allowed the comparative evaluation of ⁶⁸Ga-DOTANOC and ⁶⁸Ga-DOTATOC, with ⁶⁸Ga-DOTANOC providing better tumor-specific accumulation and renal activity. We conclude that this animal model will be of innovative value for further investigation in the imaging of NETs.

68Ga-DOTATOC and FDG PET Imaging of Preclinical Neuroblastoma Models

“…This clearly confirms that in vivo uptake of 68 Ga-DOTATOC, as assessed on PET, is actually linked to the expression of SSTR2 and not to non-specific binding. Concerning the biodistribution of 68 Ga-DOTATOC in normal organs of nude mice, our data are consistent with those reported by other teams (21,22), although the engrafted tumours in their studies were derived from the pancreatic tumour cell line AR4-2J, with low %ID/g in all normal organs except in the kidneys. In humans, 68 Ga-DOTATOC PET is significantly taken up in the pancreas, which we and another team did not observe in nude mice (23).…”

Immuno-PET Imaging of Engineered Human T Cells in Tumors

“…We additionally show that due to the heterogeneous distribution patterns of human T cells especially in large tumors, the information of uptake regarding injected dose per gram is less valuable compared with the percentage uptake of total injected dose. However, the uptake detected in our studies is still in the range of preclinical analyses of tracers demonstrated to be sufficient for clinical application (15,(39)(40)(41)(42). Moreover, the number of effector cells infused in our experiments was within the range of those previously applied in clinical trials (1)(2)(3)43).…”

Targeting Aurora Kinases with Danusertib (PHA-739358) Inhibits Growth of Liver Metastases from Gastroenteropancreatic Neuroendocrine Tumors in an Orthotopic Xenograft Model

“…Because liver metastases constitute the main clinical problem in GEP-NETs, this study extends the established knowledge of antitumor effects and mechanisms of danusertib in an orthotopic model of metastatic GEP-NETs. In accordance, an interesting orthotopic tumor model has recently been established to combine somatostatin receptor szintigraphy with MRI after injection of rat-derived pancreatic tumor cells into mouse pancreas (35). In our model, liver metastases derived from human GEP-NET cell lines retained characteristics of the GEP-NETs, that is, CgA expression and secretion as well as stimulation of angiogenesis.…”