Molecular pathology and treatment of Cushing’s disease

Principal Investigators

Prof. Dr. med. Martin Reincke
martin.reincke(at)med.uni-muenchen.de
Department Director, Professor of Internal
Medizinische Klinik und Poliklinik IV
Klinikum der Ludwig-Maximilians-Universität Munich

Prof. Dr. rer. nat. Marily Theodoropoulou
marily.theodoropoulou(at)med.uni-muenchen.de
W2 Professor of Neuroendocrinology
Medical Clinic and Policlinic IV
Ludwig-Maximilians-Universität Munich

Aims

(I) Define the role of ubiquitin specific protease 8 (USP8) in the corticotroph tumour response to the glucocorticoid feedback from the adrenals and its implication on the development of Nelson’s syndrome tumours.
(II) Explore the genetic causes of corticotrophinoma tumour formation and glucocorticoid resistance using whole genome sequencing in both Cushing’s disease and Nelson’s syndrome.
(III) Identify new therapeutics that sensitize to glucocorticoids and limit hormone hypersecretion and tumour growth in Cushing’s disease and Nelson’s syndrome

PhD/MD-Thesis

Julia Simon (2020-2022)Title: Studies on molecular mechanisms conferring aggressive behaviour to pituitary neoplasms
Xiao Chen (2019-2021)Title: Studies on the role of integrins on corticotroph tumorigenesis
Sicheng Tang (2018-2022)Title: The USP8 system as pathogenic and therapeutic target in Cushing’s disease
Awards:
2020 – European Society of Endocrinology Young Investigator Award (to Adriana Albani)
2019 – German Society of Endocrinology “Schöller‐Junkmann‐Preis” (to Luis Gustavo Perez-Rivas jointly with Isabel Weigand)
2019 – Munich Excellence Training Initiative for Physician Scientists Award to Adriana Albani
2018 – Selected oral communication and grant by the European Neuroendocrine Association (to Luis Perez-Rivas)
2018 – Poster prize of the Neuroendocrinology Section of the German Society of Endocrinology (to Paula Colón Bolea)

Publications

2020
Watts D, Stein J, Meneses A, Bechmann N, Neuwirth A, Kaden D, Krüger A, Sinha A, Ismini Alexaki V, Perez-Rivas LG, Kircher S, Martinez A, Theodoropoulou M, Eisenhofer G, Peitzsch M, El-Armouche A, Chavakis T, Wielockx B. HIF1α is a direct regulator of steroidogenesis in the adrenal gland. Cellular and Molecular Life Sciences. In press(bioRxivdoi.org/ 10.1101/2020.07.08.1917832.)
 
Albani A, Theodoropoulou M. Persistent Cushing’s Disease after Transsphenoidal Surgery: Challenges and Solutions. Exp Clin Endocrinol Diabetes. 2020. (doi: 10.1055/a-1220-6056).
 
2019
Sbiera S, Perez-Rivas LG, Taranets L, Weigand I, Flitsch J, Graf E, Monoranu CM, Saeger W, Hagel C, Honegger J, Assie G, Hermus AR, Stalla GK, Herterich S, Ronchi CL, Deutschbein T, Reincke M, Strom TM, Popov N, Theodoropoulou M, Fassnacht M. Driver mutations in USP8 wild type Cushing’s disease. Neuro Oncol. 2019;21(10):1273-1283.
 
Theodoropoulou M, Reincke M. Tumor-directed therapeutic targets in Cushing disease. J Clin Endocrinol Metab. 2019;104(3):925-933.  (Invited Review)  

Rubinstein G, Osswald A, Zopp S, Ritzel K, Theodoropoulou M, Beuschlein F, Reincke M. Therapeutic options after surgical failure in Cushing’s disease: A critical review. Best Pract Res Clin Endocrinol Metab. 2019;33(2):101270.  

Ciato D, Li R, Monteserin Garcia JL, Papst L, D’Annunzio S, Hristov M, Tichomirowa MA, Belaya Z, Rozhinskaya L, Buchfelder M, Theodoropoulou M, Paez-Pereda M, Stalla GK. Inhibition of HSF1 enhances repressive molecular mechanisms on POMC promoter. Neuroendocrinology. 2019;109(4):362-373.  

Xekouki P, Lodge EJ, Matschke J, Santambrogio A, Apps JR, Sharif A, Jacques TS, Aylwin S, Prevot V, Li R, Flitsch J, Bornstein SR, Theodoropoulou M, Andoniadou CL. Non-secreting pituitary tumours characterised by enhanced expression of YAP/TAZ. Endocr Relat Cancer. 2019;26(1):215-225.

  2018 Albani A, Theodoropoulou M, Reincke M. Genetics of Cushing’s disease. Clin Endocrinol (Oxf). 2018;88:3-12.

  Albani A, Pérez-Rivas LG, Dimopoulou C, Zopp S, Colón-Bolea P, Roeber S, Honegger J, Flitsch J, Rachinger W, Buchfelder M, Stalla GK, Herms J, Reincke M, Theodoropoulou M. The USP8 mutational status may predict long-term remission in patients with Cushing’s disease. Clin Endocrinol. 2018;88(1):3-12
 
Albani A, Perez-Rivas LG, Reincke M, Theodoropoulou M. Pathogenesis of Cushing disease: an update on the genetics of corticotrophinomas. Endocr Pract. 2018;24(10):907-914.
 
Perez-Rivas LG, Theodoropoulou M#, Puar TH, Fazel J, Stieg MR, Ferraù F, Assié G, Gadelha MR, Deutschbein  T, Fragoso MC, Kusters B, Saeger W, Honegger J, Buchfelder M, Korbonits M, Bertherat J, Stalla GK, Hermus AR, Beuschlein F, Reincke M. Somatic USP8 mutations are frequent events in corticotroph tumor progression causing Nelson’s tumor. Eur J Endocrinol. 2018; 178:59-65.