Multimodal imaging of a novel pheochromocytoma tumor model

Objective. Pheochromocytoma (PHEO) is a rare but potentially lethal neuroendocrine tumor arising from catecholamine producing chromaffin cells. Available treatment strategies are limited and, if the tumor has metastasized, not very effective. The abundant expression of peptide hormone receptors on endocrine tumor cells allows specific targeting and imaging by radioactive and highly effective anti-tumor peptide analogs. The present study focuses on the preclinical imaging and evaluation of potential therapies in the treatment of pheochromocytoma targeting peptide hormone receptors. Design and method. Somatostatin receptor 2 (SSTR2), luteinizing hormone-releasing hormone receptor (LHRH-R) and growth hormone-releasing hormone receptors (GHRH-R) were characterized by both RT-PCR and immunohistological analysis in a mouse pheochromocytoma (MPC) cell line . Based on these data, we evaluated the effects of cytotoxic peptide hormone analogs on cell viability, apoptosis, and necrosis on MPC cells. For in vivo studies, we furthermore established a new MPC mCherry transfected cell line and produced a subcutaneous mouse model of PHEO. The tumors were evaluated by multimodal imaging using PET, MRI, CT and optical imaging. Results. Our data reveal significant anti-tumor effects mediated by the cytotoxic peptide hormone analogs AN-162 and AN-238 targeting SSTR2, by the antagonist Cetrorelix targeting LHRH-R and by the cytotoxic analog AN-152 targeting as well as by the antagonist MIA-602 targeting growth GHRH-R on MPCs. Furthermore, using our newly established mouse model, we were able to visualize the growth, perfusion, metabolism, and hypoxia of MPC cell-derived subcutaneous PHEO in vivo by multimodal molecular imaging including SSTR2 PET. Additionally, histological ex vivo tumor characterization demonstrated unaltered functional peptide hormone receptor expression during in vivo tumor growth in mice. Conclusion. Our current investigation provides strong evidence for a possible future treatment of malignant PHEO using targeted peptide hormone receptor therapy. Support. This work was supported by the Deutsche Forschungsgemeinschaft (Grants BE-2607/1 (R.B. & J.P.), and ZI-1362/2-1 (C.G.Z.&G.E.).