Project B10

Prof.Dr.rer.medic.habil. Jens Pietzsch_PhD.Susan Richter_Dr. rer. nat.Christian Ziegler

Dr. Susan Richter
susan.richter(at)uniklinikum-dresden.de
Division of Clinical Neurochemistry,
Institute of Clinical Chemistry & Laboratory Medicine,
Carl Gustav Carus Faculty of Medicine at the Technische Universität Dresden

Prof. Dr. rer. medic. habil. Jens Pietzsch
j.pietzsch(at)hzdr.de
Head of Department, Professor of Pathobiochemistry
Helmholtz-Zentrum Dresden-Rossendorf (HZDR),
Institute of Radiopharmaceutical Cancer Research,
Department of Radiopharmaceutical and Chemical Biology Dresden
and Technische Universität Dresden (TUD)
Faculty of Natural Sciences
Department of Chemistry and Food Chemistry

PD Dr. rer. nat. habil. Christian G. Ziegler
Christian.Ziegler(at)uniklinikum-dresden.de
Department of Internal Medicine,
Carl Gustav Carus Faculty of Medicine at the Technische Universität Dresden

Scientific Staff:

Martin Ullrich – Postdoc
Christin Neuber – Postdoc
Markus Laube – Postdoc

Project Description:

Approximately 15% of patients with phaeochromocytoma/paraganglioma (PPGL) develop metastases, with no approved treatment options available. During the first funding period, B10 contributed significantly to improving diagnosis of patients with germline mutations predisposing to metastatic disease by applying metabologenomics in tumour samples. We made significant advances in our PPGL models, most importantly by generating a mouse model of metastatic spread. We established cyclooxygenase 2 (COX-2) as a target for adjuvant treatment, supporting our approach of testing and developing different COX-2-targeting compounds as radiosensitisers for peptide receptor endoradiotherapy (PRRT).
PRRT using [177Lu]Lu-DOTA-TATE is associated with increased overall survival as first line therapy; however, it has been reported that some patients develop extensive metastatic disease after initial response to [177Lu]Lu-DOTA-TATE treatment. Very little is known about the mechanisms of tumour control in PPGL; hence, insights into the mechanisms of radioresistance and recurrence as well as immunomodulatory effects of PRRT are essential in improving treatment efficacy through careful patient selection and adjuvant therapy.
We aim to address these areas by elevating targeting efficiency through somatostatin receptor type 2 (SSTR2) upregulation, by investigating the influence of the genetic tumour background and the microenvironment on radioresistance, by characterising radiation induced tumour metastasis and progression in mouse models, and by optimising radiosensitisation compounds. Outcomes will be complemented by results from projects B11 and B12 investigating different pathways contributing to disease aggressiveness in PPGLs. Successful completion will have immediate effects on therapy decisions for patients with metastatic PPGL.

Targeting radio- and chemo-resistance in metastatic phaeochromocytoma/ paraganglioma

(I) Investigate neoadjuvant SSTR2-inducing treatments counteracting HIF2α-associated downregulation of SSTR2 to enhance [177Lu]Lu-DOTA-TATE therapy.
(II) Establish and characterise irradiated co-culture models of MPC cells with tumour-associated macrophages with a focus on HIF2α activation, SDHB impairment, and COX-2 disruption.
(III) Explore molecular characteristics of radiation-associated metastasis in disseminated MPC metastases models with HIF2α activation, SDHB impairment, and COX-2 disruption.

PhD/MD-Thesis:

Evaluation of adjuvant radiosensitizing treatments in combination with 177Lu-DOTATATE in murine allograft models of metastatic pheochromocytomas and paragangliomas (Verena Seifert, 2017-2021)

Publications:

Seifert V, Richter S, Bechmann N, Bachmann M, Ziegler CG, Pietzsch J, Ullrich M. HIF2alpha-Associated Pseudohypoxia Promotes Radioresistance in Pheochromocytoma: Insights from 3D Models. Cancers (Basel). 2021 Jan 21;13(3):385.

Bechmann N, Moskopp ML, Ullrich M, Calsina B, Wallace PW, Richter S, Friedemann M, Langton K, Fliedner SMJ, Timmers HJLM, Nölting S, Beuschlein F, Fassnacht M, Prejbisz A, Pacak K, Ghayee HK, Bornstein SR, Dieterich P, Pietzsch J, Wielockx B, Robledo M, Qin N, Eisenhofer G. HIF2α supports pro-metastatic behavior in pheochromocytomas/paragangliomas. Endocr Relat Cancer. 2020 Nov;27(11):625-640.

Wallace PW, Conrad C, Brückmann S, Pang Y, Caleiras E, Murakami M, Korpershoek E, Zhuang Z, Rapizzi E, Kroiss M, Gudziol V, Timmers HJLM, Mannelli M, Pietzsch J, Beuschlein F, Pacak K, Robledo M, Klink B, Peitzsch M, Gill AJ, Tischler AS, de Krijger RR, Papathomas T, Aust D, Eisenhofer G, Richter S. Metabolomics, machine learning and immunohistochemistry to predict succinate dehydrogenase mutational status in phaeochromocytomas and paragangliomas. J Pathol. 2020; 251: 378–387.

Laube M, Gassner C, Kniess T, Pietzsch J. Synthesis and Cyclooxygenase Inhibition of Sulfonamide-Substituted (Dihydro)Pyrrolo[3,2,1- hi]indoles and Their Potential Prodrugs. Molecules. 2019 Oct 22;24(20):3807.

Ullrich M, Richter S, Seifert V, Hauser S, Calsina B, Martínez-Montes ÁM, Ter Laak M, Ziegler CG, Timmers H, Eisenhofer G, Robledo M, Pietzsch J. Targeting Cyclooxygenase-2 in Pheochromocytoma and Paraganglioma: Focus on Genetic Background. Cancers (Basel). 2019 May 28;11(6). pii: E743.

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. Impact of Extrinsic and Intrinsic Hypoxia on Catecholamine Biosynthesis in Absence or Presence of Hif2α in Pheochromocytoma Cells. Cancers (Basel). 2019 Apr 28;11(5). pii: E594.

Seifert V, Liers J, Kniess T, Richter S, Bechmann N, Feldmann A, Bachmann M, Eisenhofer G, Pietzsch J, Ullrich M. Fluorescent mouse pheochromocytoma spheroids expressing hypoxia-inducible factor 2 alpha: Morphologic and radiopharmacologic characterization. J Cell Biotechnol. 2019;5:135-151.

Richter S, Gieldon L, Pang Y, Peitzsch M, Huynh T, Leton R, Viana B, Ercolino T, Mangelis A, Rapizzi E, Menschikowski M, Aust D, Kroiss M, Beuschlein F, Gudziol V, Timmers HJ, Lenders J, Mannelli M, Cascon A, Pacak K, Robledo M, Eisenhofer G, Klink B. Metabolome-guided genomics to identify pathogenic variants in isocitrate dehydrogenase, fumarate hydratase, and succinate dehydrogenase genes in pheochromocytoma and paraganglioma. Genet Med. 2019 Mar;21(3):705-717.

Richter S, D’Antongiovanni V, Martinelli S, Bechmann N, Riverso M, Poitz DM, Pacak K, Eisenhofer G, Mannelli M, Rapizzi E. Primary fibroblast co-culture stimulates growth and metabolism in Sdhb-impaired mouse pheochromocytoma MTT cells. Cell Tissue Res. 2018 Dec;374(3):473-485.

Ullrich M, Liers J, Peitzsch M, Feldmann A, Bergmann R, Sommer U, Richter S, Bornstein SR, Bachmann M, Eisenhofer G, Ziegler CG, Pietzsch J. Strain-specific metastatic phenotypes in pheochromocytoma allograft mice. Endocr Relat Cancer. 2018 Oct 5;25(12):993-1004.