Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare neuroendocrine tumors derived from neural crest cells. Germline variants in approximately 20 PHEO/PGL susceptibility genes are found in about 40% of patients, half of which are found in the genes that encode succinate dehydrogenase (SDH). Patients with SDH subunit B (SDHB)-mutated PHEO/PGL exhibit a higher likelihood of developing metastatic disease, which can be partially explained by the metabolic cell reprogramming and redox imbalance caused by the mutation. Reactive oxygen species (ROS) are highly reactive molecules involved in a multitude of important signaling pathways. A moderate level of ROS production can help regulate cellular physiology; however, an excessive level of oxidative stress can lead to tumorigenic processes including stimulation of growth factor-dependent pathways and the induction of genetic instability. Tumor cells effectively exploit antioxidant enzymes in order to protect themselves against harmful intracellular ROS accumulation, which highlights the essential balance between ROS production and scavenging. Exploiting ROS accumulation can be used as a possible therapeutic strategy in ROS-scavenging tumor cells. Here, we focus on the role of ROS production in PHEO and PGL, predominantly in SDHB-mutated cases. We discuss potential strategies and approaches to anticancer therapies by enhancing ROS production in these difficult-to-treat tumors.

• Keywords
• metastatic pheochromocytoma, paraganglioma, reactive oxygen species, succinate dehydrogenase,
• Publication type
• Journal Article MeSH

Purpose: Cluster I pheochromocytomas and paragangliomas (PCPGs) tend to develop malignant transformation, tumor recurrence, and multiplicity. Transcriptomic profiling suggests that cluster I PCPGs and other related tumors exhibit distinctive changes in the tricarboxylic acid (TCA) cycle, the hypoxia signaling pathway, mitochondrial electron transport chain, and methylation status, suggesting that therapeutic regimen might be optimized by targeting these signature molecular pathways.Experimental Design: In the present study, we investigated the molecular signatures in clinical specimens from cluster I PCPGs in comparison with cluster II PCPGs that are related to kinase signaling and often present as benign tumors.Results: We found that cluster I PCPGs develop a dependency to mitochondrial complex I, evidenced by the upregulation of complex I components and enhanced NADH dehydrogenation. Alteration in mitochondrial function resulted in strengthened NAD+ metabolism, here considered as a key mechanism of chemoresistance, particularly, of succinate dehydrogenase subunit B (SDHB)-mutated cluster I PCPGs via the PARP1/BER DNA repair pathway. Combining a PARP inhibitor with temozolomide, a conventional chemotherapeutic agent, not only improved cytotoxicity but also reduced metastatic lesions, with prolonged overall survival of mice with SDHB knockdown PCPG allograft.Conclusions: In summary, our findings provide novel insights into an effective strategy for targeting cluster I PCPGs, especially those with SDHB mutations. Clin Cancer Res; 24(14); 3423-32. ©2018 AACR.

• MeSH
• Apoptosis genetics   MeSH
• Models, Biological MeSH
• Cell Cycle genetics   MeSH
• Drug Resistance, Neoplasm genetics   MeSH
• Molecular Targeted Therapy MeSH
• Pheochromocytoma drug therapy   genetics   metabolism   pathology   MeSH
• Humans MeSH
• Mitochondria metabolism   MeSH
• Disease Models, Animal MeSH
• Mutation MeSH
• Mice MeSH
• NAD metabolism   MeSH
• Cell Line, Tumor MeSH
• DNA Repair * MeSH
• Paraganglioma drug therapy   genetics   metabolism   pathology   MeSH
• Poly(ADP-ribose) Polymerase Inhibitors pharmacology   therapeutic use   MeSH
• Poly(ADP-ribose) Polymerases metabolism   MeSH
• Antineoplastic Agents pharmacology   therapeutic use   MeSH
• Signal Transduction drug effects   MeSH
• Succinate Dehydrogenase genetics   MeSH
• Xenograft Model Antitumor Assays MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH
• Names of Substances
• NAD MeSH
• Poly(ADP-ribose) Polymerase Inhibitors MeSH
• Poly(ADP-ribose) Polymerases MeSH
• Antineoplastic Agents MeSH
• SDHB protein, human MeSH Browser
• Succinate Dehydrogenase MeSH