Combined peptide receptor cytotoxic/radionuclide therapy for the treatment of metastatic pheochromocytoma
Final Report Abstract
The DFG project was a cooperative project between the Institute of Radiopharmaceutical Cancer Research at the Helmholtz-Zentrum Dres den-Rossendorf (HZDR) and the University Hospital Dresden. Important features of pheochromocytoma (PCC) and paraganglioma (PGL), which belong to the group of neuroendocrine tumors , are catecholamine production and overexpression of somatostatin receptor type 2 (SSTR2). Somatostatin receptors are G protein coupled receptors and the downstream s ignalling of thes e receptors is an interesting drugable target for neuroendocrine neoplams. Within our project we perform metabolic PET imaging with established radiotracers, such as [18F]FDOPA, [18F]FDG, [64Cu]Cu-DOTATATE and various others to functionally characterize the tumor and the tumor microenvironment. The first part of of our studies has been the es tablishment and characterization of different metastasis models for PCC/PGLs . This work demonstrates the dependence of metastasic pattern on the immunologic background of different mouse strains and characterized features such as renal monoamine excretion, SSTR2 status and histology of murine MPC metastases models. Secondly, a therapeutic approach was performed in T-cell-deficient NMRI-nu mice bearing subcutaneous MPCLUC/GZ tumors , comparing a single-dose with a fractionated endoradionuclide therapy us ing [177Lu]Lu-DOTATAE. Tumor growth was monitored using caliper measurement and bioluminescence imaging. The fractionated treatment group showed a slight benefit toward the single treated group with regard to tumor growth, which res embles the clinic situation of patients treated with [177Lu]Lu-DOTA-(Tyr3)octreotate (DOTATATE). However, fractionated treatment of animals showed a significant leucocytopenia compared to control animals. Both single-dose and fractionated treatment showed increased urinary protein levels in mice (albumin, whole protein) compared to control, indicating the nephrotoxicity of endoradiotherapy. Finally we are finishing a further publication on epigenetic regulation of SSTR2 expression as novel combinational / adjuvant therapeutic applications for PCC/PGLs with insufficient SSTR2 levels. Particularly with regard to metastatic disease, no effective treatment is available. Also the promising approach and clinical standard of SSTR2-targeted radionuclide therapy using e.g. [177Lu]Lu-DOTATATE, often shows insufficient res ults and is regarded as palliative. Therefore it is necessary to evaluate novel adjuvant approaches, that could enhance therapeutic outcome by e.g. increasing SSTR2 expression. In vitro as well as in vivo studies were performed in two different mouse pheochromocytoma cell lines including cell viability assay, western blot analyses, radiotracer uptake studies as well as biodistribution, PET and SPECT investigations. These investigations demonstrated that functional upregulation of SSTR2 using epigenetic modifiers is achievable in PCC/PGLs and enhances the outcome of [177Lu]Lu-DOTATATE endoradiotherapy.
Publications
- (2016) Entwicklung und Charakterisierung von murinen Tumormodellen und präklinische theragnostische Untersuchungen zu Somatostatin-Rezeptor-vermittelten Therapien des metastasierenden Phäochromozytoms. Diss., Technische Universität Dresden, Fakultät Mathematik und Naturwissenschaften, Fachrichtung Chemie und Lebensmittelchemie
Ullrich, Martin
- (2016) Multimodal Somatostatin Receptor Theranostics Us ing [64Cu]Cu - /[177Lu]Lu-DOTA-(Tyr3)octreotate and AN-238 in a Mous e Pheochromocytoma Model. Theranostics. 6:650-665
Ullrich M, Bergmann R, Peitzsch M, Zenker EF, Cartellieri M, Bachmann M, Ehrhart-Bornstein M, Block NL, Schally AV, Eis enhofer G, Bornstein SR, Pietzsch J, Ziegler CG
(See online at https://dx.doi.org/10.7150%2Fthno.14479) - (2018) Strains pecific metastatic phenotypes in pheochromocytoma allograft mice. Endocr Relat Cancer. 25:993-1004
Ullrich M, Liers J, Peitzsch M, Feldmann A, Bergmann R, Sommer U, Richter S, Bornstein SR, Bachmann M, Eisenhofer G, Ziegler CG, Pietzsch J
(See online at https://doi.org/10.1530/ERC-18-0136) - (2019) Current management of pheochromocytoma/paraganglioma: A guide for the practicing clinician in the era of precision medicine. Cancers (Basel). 11:1505
Nölting S, Ullrich M, Pietzsch J, Ziegler CG, Eisenhofer G, Grossman, Pacak K
(See online at https://doi.org/10.3390/cancers11101505) - (2019) Impact of extrinsic and intrinsic hypoxia on catecholamine biosynthesis in absence or pres ence of Hif2α in pheochromocytoma cells. Cancers (Basel) 11:594
Bechmann N, Poser I, Seifert V, Greunke C, Ullrich M, Qin N, Walch A, Peitzsch M, Robledo M, Pacak K, Pietzsch J, Richter S, Eisenhofer G
(See online at https://doi.org/10.3390/cancers11050594) - (2019) Novel preclinical models and theranostic strategies for pheochromocytoma. [Habilitationsschrift; Technische Universität Dresden, Fakultät Medizin, Fachrichtung Innere Medizin/Endokrinologie]
Ziegler, Christian G.
- (2019) Targeting cyclooxygenase-2 in pheochromocytoma and paraganglioma: focus on genetic background. Cancers (Basel) 11:743
Ullrich M, Richter S, Seifert V, Hauser S, Calsina B, Martínez-Montes AM, ter Laak M, Ziegler CG, Timmers H, Eisenhofer G, Robledo M, Pietzsch J.
(See online at https://doi.org/10.3390/cancers11060743) - (2020) Three-dimensional cell culture systems in radiopharmaceutical cancer research. Cancers (Basel). 12:2765
Doctor A, Seifert S, Ullrich M, Hauser S, Pietzsch J
(See online at https://doi.org/10.3390/cancers12102765)
