Evaluation of a novel fluorescence-based animal model of pheochromocytoma for theragnostic investigations

Abstract

Pheochromocytoma (PHEO) are potentially lethal tumors of adrenal and extra-adrenal chromaffin cells. Available treatment strategies for malignant PHEO are limited. Interestingly, peptide hormone receptors are frequently overexpressed on PHEO and can be used as specific targets for highly effective cytotoxic and radiolabeled anti-tumor peptide analogs. Here, we focused on the establishment and characterization of a novel preclinical fluorescence-based mouse model of PHEO in order to evaluate combined therapies of malignant pheochromocytoma. In previous in vitro studies we demonstrated strong anti-tumor effects of various peptide analogs specifically targeting SSTR2 and LHRH-R in mouse pheochromocytoma cell lines. These neuropeptide receptors were found to be abundantly expressed also on human PHEO samples studied. Furthermore, we examined the expression of these receptors as potential anti-tumor targets in vivo and ex vivo. To this end we established a subcutaneous mouse model of PHEO based on the injection of mCherry-expressing MPCs into the shoulders of athymic nude mice. Tumor development was followed by multimodal in vivo imaging, including fluorescence, PET, CT and MRI. Additionally, we analyzed urinary catecholamines by recently established LC-MS/MS. Both the SSTR2 and LHRH-R are still abundantly expressed in the tumors and could thus be used as therapeutic targets in ongoing pre-clinical studies. In summery, our current work resulted in the establishment of both an appropriate PHEO model system and methodology for our planned combined peptide receptor cytotoxic/radionuclide therapy studies.