Hypoxia and MYC/MAX signaling pathways in chromaffin tumourigenesis

• Applicant: Professor Graeme Eisenhofer, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2011 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 189897882

• Final Report Year: 2019

Final Report Abstract

This translational project directed at pheochromocytomas and paragangliomas (PPGLs), and involving patients with PPGLs and chromaffin cell model systems, focused on exploring the mechanisms linking germline mutations to tumorigenesis and distinct clinical presentations of patients with chromaffin cell tumors. Links between hypoxia (particularly related to HIF2α), mitochondrial energy and catecholamine biosynthetic and secretory pathways were examined according to an underlying hypothesis that different types of PPGLs arise from distinct chromaffin progenitor cells according to specific programming of developmental pathways that offer insight for novel therapies and markers for diagnosis. Over 40 peerreviewed scientific publications and one patent arose from the project over the final period of KFO252 funding from 2014 onwards. These publications related to several areas: 1. development, technical improvement and promulgation of tests for diagnosis of PPGLs that are now used widely around the world; 2. development of a patented device to improve diagnostic accuracy of the aforementioned tests; 3. development of mass spectrometry Krebs cycle metabolite profiles to assist with the interpretation of genetic test results and guide genetic testing of patients with PPGLs; 4. development of new technologies for genetiic testing in patients with PPGLs; 4. identification of novel changes to the genome (epigenetic hypermethylation of the promoter region of the SDHC gene) that result in multifocal paraganglioma; 5. identification of mutations in new tumor-susceptibility genes; 6. characterization of underlying genetic differences responsible for childhood and early adulthood versus later adulthood PPGLs; 7. identification of signaling pathways downstream from mutations of specific genes responsible for different clinical presentations of patients with PPGLs; 8. establishment of cell line and mouse model systems for testing hypotheses and drugs for potential treatment of patients with metastatic PPGLs. In addition to improving the diagnosis and managment of patients with PPGLs worldwide, other outcomes of this project included establishment of international networks for multicenter studies of PPGLs and the training of and associated gain in expertise of young clinicians and bench level scientists, including several who now have doctorates or other degrees and qualifications.

Publications

• Krebs cycle metabolite profiling for identification and stratification of pheochromocytomas / paragangliomas due to succinate dehydrogenase deficiency. J Clin Endocrinol Metab. 2014 Oct;99(10):3903-11
  Richter S, Peitzsch M, Rapizzi E, Lenders JW, Qin N, de Cubas AA, Schiavi F, Rao JU, Beuschlein F, Quinkler M, Timmers HJ, Opocher G, Mannelli M, Pacak K, Robledo M, Eisenhofer G
  
• Neuroendocrine cancer. Closing the GAPP on predicting metastases. Nat Rev Endocrinol. 2014 Jun;10(6):315-6
  Eisenhofer G, Tischler AS
  
• Opposing effects of HIF1α and HIF2α on chromaffin cell phenotypic features and tumor cell proliferation: Insights from MYC-associated factor X. Int J Cancer. 2014 Nov 1;135(9):2054-64
  Qin N, de Cubas AA, Garcia-Martin R, Richter S, Peitzsch M, Menschikowski M, Lenders JW, Timmers HJ, Mannelli M, Opocher G, Economopoulou M, Siegert G, Chavakis T, Pacak K, Robledo M, Eisenhofer G
  
• Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014 Jun;99(6):1915-42
  Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, Naruse M, Pacak K, Young WF Jr
  
• Lack of utility of SDHB mutation testing in adrenergic metastatic phaeochromocytoma. Eur J Endocrinol. 2015 Feb;172(2):89-95
  Sue M, Martucci V, Frey F, Lenders JM, Timmers HJ, Peczkowska M, Prejbisz A, Swantje B, Bornstein SR, Arlt W, Fassnacht M, Beuschlein F, Robledo M, Pacak K, Eisenhofer G
  
• Epigenetic Mutation of the Succinate Dehydrogenase C Promoter in a Patient With Two Paragangliomas. J Clin Endocrinol Metab. 2016 Feb;101(2):359-63
  Richter S, Klink B, Nacke B, de Cubas AA, Mangelis A, Rapizzi E, Meinhardt M, Skondra C, Mannelli M, Robledo M, Menschikowski M, Eisenhofer G
  
• Characteristics of Pediatric vs Adult Pheochromocytomas and Paragangliomas. J Clin Endocrinol Metab. 2017 Apr 1;102(4):1122-1132
  Pamporaki C, Hamplova B, Peitzsch M, Prejbisz A, Beuschlein F, Timmers HJLM, Fassnacht M, Klink B, Lodish M, Stratakis CA, Huebner A, Fliedner S, Robledo M, Sinnott RO, Januszewicz A, Pacak K, Eisenhofer G
  
• Metabologenomics of Phaeochromocytoma and Paraganglioma: An Integrated Approach for Personalised Biochemical and Genetic Testing. Clin Biochem Rev. 2017 Apr;38(2):69-100
  Eisenhofer G, Klink B, Richter S, Lenders JW, Robledo M
  
• Plasma methoxytyramine: clinical utility with metanephrines for diagnosis of pheochromocytoma and paraganglioma. Eur J Endocrinol. 2017 Aug;177(2):103-113
  Rao D, Peitzsch M, Prejbisz A, Hanus K, Fassnacht M, Beuschlein F, Brugger C, Fliedner S, Langton K, Pamporaki C, Gudziol V, Stell A, Januszewicz A, Timmers HJLM, Lenders JWM, Eisenhofer G
  
• Biochemical Diagnosis of Chromaffin Cell Tumors in Patients at High and Low Risk of Disease: Plasma versus Urinary Free or Deconjugated O-Methylated Catecholamine Metabolites. Clin Chem. 2018 Nov;64(11):1646-1656
  Eisenhofer G, Prejbisz A, Peitzsch M, Pamporaki C, Masjkur J, Rogowski-Lehmann N, Langton K, Tsourdi E, Pęczkowska M, Fliedner S, Deutschbein T, Megerle F, Timmers HJLM, Sinnott R, Beuschlein F, Fassnacht M, Januszewicz A, Lenders JWM
  
• Device for adjusting and determining the blood flow plateau. DE 10 2014 104 167.4 Approved in 2018 for US, Europe and other nations
  Eisenhofer G, Pamporaki C, Filippatos A
  
• Metabolome-guided genomics to identify pathogenic variants in isocitrate dehydrogenase, fumarate hydratase, and succinate dehydrogenase genes in pheochromocytoma and paraganglioma. Genet Med. 2018 Jul 27
  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
  
• Adrenomedullary function, obesity and permissive influences of catecholamines on body mass in patients with chromaffin cell tumours. Int J Obes (Lond). 2019 Feb;43(2):263-275
  An Y, Reimann M, Masjkur J, Langton K, Peitzsch M, Deutschbein T, Fassnacht M, Rogowski-Lehmann N, Beuschlein F, Fliedner S, Stell A, Prejbisz A, Januszewicz A, Lenders J, Bornstein SR, Eisenhofer G