MON-199 Targeting Pheochromocytoma/Paraganglioma with Polyamine Inhibitors

Background: Pheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors that are mostly benign. Metastatic disease occurs in about 10% of cases, 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 with very little treatment options. To find a new treatment strategy, we utilized a metabolomics approach to identify unique metabolic pathways. A metabolomic analysis was performed on human hPheo1 cells and shRNA SDHB knockdown hPheo1 (hPheo1 SDHB KD) cells. Additional analysis of 50 human fresh frozen PCC/PGL samples was conducted. Since the polyamine pathway surfaced in the metabolomics analysis, we hypothesized that treatment with polyamine inhibitors would be an effective option for aggressive PCC/PGL tumors. In vitro studies using N1,N11-diethylnorspermine (DENSPM) and N1,N12- diethylspermine (DESPM) treatments were carried out. DENSPM efficacy was assessed in xenograft models. 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 tumor tissues compared to their SDHB wild-type 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 inhibitors significantly inhibited hPheo1 cell growth and led to growth inhibition in xenograft mouse models 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.