Targeting pheochromocytoma/paraganglioma with polyamine inhibitors.

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. 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. 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. 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. Copyright © 2020 Elsevier Inc. All rights reserved.

Citation

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, Karel Pacak, Sergei G Tevosian, Hans K Ghayee. Targeting pheochromocytoma/paraganglioma with polyamine inhibitors. Metabolism: clinical and experimental. 2020 Sep;110:154297

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PMID: 32562798

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