Targeting pheochromocytoma/paraganglioma with polyamine inhibitors

Sudhir Kumar Rai; Fernando Bril; Heather M Hatch; Yiling Xu; Laura Shelton; Srilaxmi Kalavalapalli; Arielle Click; Douglas Lee; Chris Beecher; Austin Kirby; Kimi Kong; Jose Trevino; Abhishek Jha; Shashank Jatav; Kriti Kriti; Soumya Luthra; Timothy J Garrett; Joy Guingab-Cagmat; Daniel Plant; Prodip Bose; Kenneth Cusi; Robert A Hromas; Arthur S Tischler; James F Powers; Priyanka Gupta; James Bibb; Felix Beuschlein; Mercedes Robledo; Bruna Calsina; Henri Timmers; David Taieb; Matthias Kroiss; Susan Richter; Katharina Langton; Graeme Eisenhofer; Raymond Bergeron Jr; Karel Pacak; Sergei G Tevosian; Hans K Ghayee

doi:10.1016/j.metabol.2020.154297

Targeting pheochromocytoma/paraganglioma with polyamine inhibitors

Metabolism. 2020 Sep:110:154297. doi: 10.1016/j.metabol.2020.154297. Epub 2020 Jun 18.

Authors

Sudhir Kumar Rai¹, Fernando Bril², Heather M Hatch³, Yiling Xu¹, Laura Shelton⁴, Srilaxmi Kalavalapalli¹, Arielle Click⁵, Douglas Lee⁶, Chris Beecher⁷, Austin Kirby⁸, Kimi Kong⁸, Jose Trevino⁹, Abhishek Jha¹⁰, Shashank Jatav¹⁰, Kriti Kriti¹⁰, Soumya Luthra¹⁰, Timothy J Garrett¹¹, Joy Guingab-Cagmat¹¹, Daniel Plant¹², Prodip Bose¹², Kenneth Cusi², Robert A Hromas⁸, Arthur S Tischler¹³, James F Powers¹³, Priyanka Gupta¹⁴, James Bibb¹⁴, Felix Beuschlein¹⁵, Mercedes Robledo¹⁶, Bruna Calsina¹⁶, Henri Timmers¹⁷, David Taieb¹⁸, Matthias Kroiss¹⁹, Susan Richter²⁰, Katharina Langton²¹, Graeme Eisenhofer²², Raymond Bergeron Jr²³, Karel Pacak²⁴, Sergei G Tevosian²⁵, Hans K Ghayee²⁶

Affiliations

¹ Department of Medicine, Division of Endocrinology, University of Florida, Gainesville, FL, USA.
² Department of Medicine, Division of Endocrinology, University of Florida and Malcom Randall VA Medical Center, Gainesville, FL, USA.
³ Department of Physiological Sciences, University of Florida, Gainesville, FL, USA.
⁴ Scientific Project Development, Human Metabolome Technologies, Boston, MA, USA.
⁵ Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁶ Omic Insight, LLC, Durham, NC, USA.
⁷ IROA Technologies, Chapel Hill, NC, USA.
⁸ Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA.
⁹ Department of Surgery, University of Florida, Gainesville, FL, USA.
¹⁰ Elucidata, Cambridge, MA, USA.
¹¹ Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
¹² Department of Physiological Sciences, University of Florida, Malcom Randall VA Medical Center, Gainesville, FL, USA.
¹³ Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston, MA, USA.
¹⁴ Department of Surgery, University of Alabama, Birmingham, AL, USA.
¹⁵ Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, UniversitätsSpital Zurich, Zurich, Switzerland.
¹⁶ Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center (CNIO), and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
¹⁷ Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.
¹⁸ Department of Nuclear Medicine, La Timone University Hospital, European Center for Research in Medical Imaging, Aix Marseille Université, Marseille, France.
¹⁹ Department of Internal Medicine, Division of Endocrinology and Diabetology, University Hospital Würzburg, University of Würzburg, Würzburg, Germany.
²⁰ Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
²¹ Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
²² Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; Division of Clinical Neurochemistry, Institute of Clinical Chemistry and Laboratory Medicine, and Department of Medicine, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
²³ Department of Medicinal Chemistry, University of Florida, Gainesville, FL, USA.
²⁴ Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
²⁵ Department of Physiological Sciences, University of Florida, Gainesville, FL, USA. Electronic address: stevosian@ufl.edu.
²⁶ Department of Medicine, Division of Endocrinology, University of Florida and Malcom Randall VA Medical Center, Gainesville, FL, USA. Electronic address: hans.ghayee@medicine.ufl.edu.

Abstract

Background: Pheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors that are mostly benign. Metastatic disease does occur in about 10% of cases of PCC and up to 25% of PGL, and for these patients no effective therapies are available. Patients with mutations in the succinate dehydrogenase subunit B (SDHB) gene tend to have metastatic disease. We hypothesized that a down-regulation in the active succinate dehydrogenase B subunit should result in notable changes in cellular metabolic profile and could present a vulnerability point for successful pharmacological targeting.

Methods: Metabolomic analysis was performed on human hPheo1 cells and shRNA SDHB knockdown hPheo1 (hPheo1 SDHB KD) cells. Additional analysis of 115 human fresh frozen samples was conducted. In vitro studies using N¹,N¹¹-diethylnorspermine (DENSPM) and N¹,N¹²- diethylspermine (DESPM) treatments were carried out. DENSPM efficacy was assessed in human cell line derived mouse xenografts.

Results: Components of the polyamine pathway were elevated in hPheo1 SDHB KD cells compared to wild-type cells. A similar observation was noted in SDHx PCC/PGLs tissues compared to their non-mutated counterparts. Specifically, spermidine, and spermine were significantly elevated in SDHx-mutated PCC/PGLs, with a similar trend in hPheo1 SDHB KD cells. Polyamine pathway inhibitors DENSPM and DESPM effectively inhibited growth of hPheo1 cells in vitro as well in mouse xenografts.

Conclusions: This study demonstrates overactive polyamine pathway in PCC/PGL with SDHB mutations. Treatment with polyamine pathway inhibitors significantly inhibited hPheo1 cell growth and led to growth suppression in xenograft mice treated with DENSPM. These studies strongly implicate the polyamine pathway in PCC/PGL pathophysiology and provide new foundation for exploring the role for polyamine analogue inhibitors in treating metastatic PCC/PGL. PRéCIS: Cell line metabolomics on hPheo1 cells and PCC/PGL tumor tissue indicate that the polyamine pathway is activated. Polyamine inhibitors in vitro and in vivo demonstrate that polyamine inhibitors are promising for malignant PCC/PGL treatment. However, further research is warranted.

Keywords: DENSPM; DESPM; Paraganglioma (PGL); Pheochromocytoma (PCC); Polyamine; SDHB.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adrenal Gland Neoplasms / drug therapy*
Adrenal Gland Neoplasms / genetics
Adrenal Gland Neoplasms / metabolism
Animals
Biogenic Polyamines / antagonists & inhibitors*
Biogenic Polyamines / metabolism
Cell Line, Tumor
Humans
Male
Metabolomics
Mice
Mutation
Paraganglioma / drug therapy*
Paraganglioma / genetics
Paraganglioma / metabolism
Pheochromocytoma / drug therapy*
Pheochromocytoma / genetics
Pheochromocytoma / metabolism
Succinate Dehydrogenase / genetics
Xenograft Model Antitumor Assays

Substances

Biogenic Polyamines
SDHB protein, human
Succinate Dehydrogenase

Abstract

Publication types

MeSH terms

Substances

Grants and funding