Combined peptide receptor cytotoxic/radionuclide therapy for the treatment of metastatic pheochromocytoma

• Applicants: Professor Dr. Jens Pietzsch, since 3/2019; Dr. Christian G. Ziegler, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2012 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 206838255

Within the expiring DFG projects we demonstrated significant anti-tumor effects of peptide analogs targeting somatostatin receptor 2 (SSTR2), growth hormone-releasing hormone receptor (GHRHR), and luteinizing hormone-releasing hormone receptor (LHRHR), on murine pheochromocytoma (PHEO) cell lines. In order to test selected anti-tumor peptides in vivo, we establishing the NMRI nu/nu-MPC-mCherry model of PHEO providing comprehensive physiologic and imaging readouts for theranostic investigations. Our pilot in vivo therapy studies revealed significant anti-tumor effects of the doxorubicin-conjugated SST analog AN-238 at 0.2 µmol/kg, doxorubicin at 6.9 µmol/kg, and the radiolabeled SST analog [177Lu]Lu-DOTA-TATE at 75 MBq/animal. Based on these findings, we plan to establish advanced mouse models of PHEO, presenting different patterns of organ lesions at clinically relevant metastatic sites, after subcutaneous and systemic injection of luciferase-labeled murine PHEO cells into C.B-17/IcrHsd-PrkdcscidLystbg-J (SCID/beige) mice. We plan to employ the subcutaneous tumor model for performing a [177Lu]Lu-DOTA-TATE dose escalation study. The tumor model presenting a reproducible metastatic pattern comparable to typical human metastatic PHEO will be employed for evaluating a novel theranostic, fractionated, and multimodal SSTR2-targeting therapy concept based on a) the diagnostic radiopeptide [68Ga]Ga-DOTA-TATE and b) the therapeutic radiopeptide [177Lu]Lu-DOTA-TATE as well as c) the cytotoxic peptide analog AN-238. Therapeutic interventions will be studied in single and combined regimen for achieving long-lasting tumor control of organ lesions and a rapid translation into precise personalized medicine.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Dr. Ralf Bergmann, until 3/2019