Benutzerspezifische Werkzeuge

Progress Report 2013

KFO252_long

Progress Report 2013: Project 10 – Novel Strategies of Targeted Multimodal/Combined Therapy of Pheochromocytoma

Background

Pheochromocytoma (PHEO) is a rare but potentially lethal neuroendocrine tumour arising from chromaffin cells in the adrenal medulla and tumours of extra-adrenal sympathetic and parasympathetic paraganglia producing catecholamines. PHEO frequently overexpresses peptide hormone receptors, like SSTR2, LHRH-R; α-, β-, and dopamine receptors, cell membrane norepinephrine and LAT1-transporter systems that all are potential targets for highly specific radionuclide-based and cytotoxic therapeutics. PHEO represents tumours with oxidative phosphorylation defects due to the mutation of succinate dehydrogenase, which results in the shift from oxidative phosphorylation to aerobic glycolysis. This is a supporting factor to overexpress mediators of chemo- or radioresistence, e.g., the cyclooxygenase-2 in PHEO. The multidrug and toxic compound extrusion (MATE) family transporters in PHEO prevent long-time therapy by cytostatic compounds. All these PHEO characteristics increase the therapy resistance of this tumour entity. Therefore, is the combination of targeted radiotherapy with modulation of the radioresistance by, e.g., selective COX-2 inhibitors and cytotoxic therapy including receptor. The project essentially will include peptide and metabolic tumour imaging to functionally evaluate the tumour control.


Achievements

During last year were the basics for preclinical PHEO therapy experiments established. The peptide receptor expression pattern was shown on rat PC-12 cells (Ziegler CG et al., 2009) and mouse pheochromocytoma cell lines, MPC and MTT cells (Ziegler et al., 2012), and it could be proved significant anti-tumour effects of various peptide analogues specifically targeting the somatostatin receptor 2 (sst2), the growth hormone-releasing hormone receptor (GHRHR) as well as the luteinizing hormone-releasing hormone receptor (LHRHR). However, we especially developed a new mouse PHEO cell line stably expressing mCherry (MPC-mCherry) to assess the cellularity in transplanted tumour models in vivo for better tumour evaluation. Using these MPC-mCherry a subcutaneous tumour model on athymic NMRI nu/nu mice was established. The tumour expresses in vitro and in vivo the similar neuropeptide hormone receptors as in the other PHEO cell lines that could be used as tumour cell specific membrane targets. This allows a fast access of the targeting peptides and tumour treatment by specific radiotherapy in combination with long-lasting and highly effective peptide analogues (cytotoxic peptides), specifically targeting these aberrantly expressed receptors. In pilot studies it was shown that Lu-177 labelled peptides will be accumulated in the tumours. An important step was the establishment of quantitative Optical Fluorescence Imaging of the MPC-mCherry tumours as prerequisite of tumour growth velocity measurements that represents the basis for therapy control evaluation. The developed metabolic, hypoxic and perfusion in vivo small animal imaging by PET, SPECT and MRI will allow to measure biochemical changes in the tumours before the size will be changed under therapy. The multimodality imaging in vivo and ex vivo could evidence the high expression of the target structures over time. The typical biomarkers, the amount and class of catecholamines in urine, correlate well with the tumour development. The overexpression of the COX-2 in PHEO is the basis of the modulation of the radiosensitivity by application of novel selective cox-2 inhibitors (coxibs) that contain a nitric oxide-releasing moiety. This effect was proven in vitro on other cell lines.