Head and neck paragangliomas Paragangliomas and pheochromocytomas are rare, mostly benign neuroendocrine tumors, which are embryologically derived from neural crest cells of the autonomic nervous system. Paragangliomas are essentially the extra-adrenal counterparts of pheochromocytomas. As such this family of tumors can be subdivided into head and neck paragangliomas, pheochromocytomas and thoracic and abdominal extra-adrenal paragangliomas. Ten out of fifteen genes that contribute to the development of paragangliomas are more susceptible to the development of head and neck paragangliomas when mutated. Gene expression profiling revealed that pheochromocytomas and paragangliomas can be classified into two main clusters (C1 and C2) based on transcriptomes. These groups were defined according to their mutational status and as such strongly associated with specific tumorigenic pathways. The influence of the main genetic drivers on the somatic molecular phenotype was shown by DNA methylation and miRNA profiling. Certain subunits of succinate dehydrogenase (SDHx), von Hippel-Lindau (VHL) and transmembrane protein 127 (TMEM127) still have the highest impact on development of head and neck paragangliomas. The link between RAS proteins and the formation of pheochromocytoma and paragangliomas is clear due to the effect of receptor tyrosine-protein kinase (RET) and neurofibromatosis type 1 (NF1) in RAS signaling and recent discovery of the role of HRAS. The functions of MYC-associated factor X (MAX) and prolyl hydroxylase 2 (PHD2) mutations in the contribution to the pathogenesis of paragangliomas still remain unclear. Ongoing studies give us insight into the incidence of germline and somatic mutations, thus offering guidelines to early detection. Furthermore, these also show the risk of mistakenly assuming sporadic cases in the absence of definitive family history in head and neck paragangliomas.

• MeSH
• Humans MeSH
• Mutation MeSH
• Head and Neck Neoplasms * genetics   MeSH
• Paraganglioma * genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Metastatic pheochromocytoma continues to be an incurable disease, and treatment with conventional cytotoxic chemotherapy offers limited efficacy. In the present study, we evaluated a novel topoisomerase I inhibitor, LMP-400, as a potential treatment for this devastating disease. We found a high expression of topoisomerase I in human metastatic pheochromocytoma, providing a basis for the evaluation of a topoisomerase 1 inhibitor as a therapeutic strategy. LMP-400 inhibited the cell growth of established mouse pheochromocytoma cell lines and primary human tumor tissue cultures. In a study performed in athymic female mice, LMP-400 demonstrated a significant inhibitory effect on tumor growth with two drug administration regimens. Furthermore, low doses of LMP-400 decreased the protein levels of hypoxia-inducible factor 1 (HIF-1α), one of a family of factors studied as potential metastatic drivers in these tumors. The HIF-1α decrease resulted in changes in the mRNA levels of HIF-1 transcriptional targets. In vitro, LMP-400 showed an increase in the growth-inhibitory effects in combination with other chemotherapeutic drugs that are currently used for the treatment of pheochromocytoma. We conclude that LMP-400 has promising antitumor activity in preclinical models of metastatic pheochromocytoma and its use should be considered in future clinical trials.

• MeSH
• Benzodioxoles administration & dosage   pharmacology   MeSH
• PC12 Cells MeSH
• DNA Topoisomerases, Type I metabolism   MeSH
• Hypoxia-Inducible Factor 1, alpha Subunit genetics   metabolism   MeSH
• Pheochromocytoma drug therapy   enzymology   pathology   MeSH
• Cell Hypoxia MeSH
• Topoisomerase I Inhibitors administration & dosage   pharmacology   MeSH
• Isoquinolines administration & dosage   pharmacology   MeSH
• Rats MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Mice, Nude MeSH
• Cell Line, Tumor MeSH
• Tumor Cells, Cultured MeSH
• Liver Neoplasms drug therapy   enzymology   secondary   MeSH
• Adrenal Gland Neoplasms drug therapy   enzymology   pathology   MeSH
• Lung Neoplasms drug therapy   enzymology   secondary   MeSH
• Reverse Transcriptase Polymerase Chain Reaction MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents pharmacology   MeSH
• Gene Expression Regulation, Neoplastic drug effects   MeSH
• Drug Synergism MeSH
• Dose-Response Relationship, Drug MeSH
• Blotting, Western MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, N.I.H., Intramural MeSH
• Names of Substances
• Benzodioxoles MeSH
• DNA Topoisomerases, Type I MeSH
• Hypoxia-Inducible Factor 1, alpha Subunit MeSH
• HIF1A protein, human MeSH Browser
• Topoisomerase I Inhibitors MeSH
• Isoquinolines MeSH
• NSC 724998 MeSH Browser
• Antineoplastic Agents MeSH

Warburg's metabolic hypothesis is based on the assumption that a cancer cell's respiration must be under attack, leading to its damage, in order to obtain increased glycolysis. Although this may not apply to all cancers, there is some evidence proving that primarily abnormally functioning mitochondrial complexes are indeed related to cancer development. Thus, mutations in complex II (succinate dehydrogenase (SDH)) lead to the formation of pheochromocytoma (PHEO)/paraganglioma (PGL). Mutations in one of the SDH genes (SDHx mutations) lead to succinate accumulation associated with very low fumarate levels, increased glutaminolysis, the generation of reactive oxygen species, and pseudohypoxia. This results in significant changes in signaling pathways (many of them dependent on the stabilization of hypoxia-inducible factor), including oxidative phosphorylation, glycolysis, specific expression profiles, as well as genomic instability and increased mutability resulting in tumor development. Although there is currently no very effective therapy for SDHx-related metastatic PHEOs/PGLs, targeting their fundamental metabolic abnormalities may provide a unique opportunity for the development of novel and more effective forms of therapy for these tumors.

• Keywords
• SDHx, Warburg effect, gastrointestinal stromal tumor, glycolysis, hypoxia, paraganglioma, pheochromocytoma, pseudohypoxia, reactive oxygen species, renal cell carcinoma, succinate dehydrogenase,
• MeSH
• Pheochromocytoma genetics   metabolism   MeSH
• Cell Physiological Phenomena MeSH
• Glycolysis MeSH
• Humans MeSH
• Mutation genetics   MeSH
• Adrenal Gland Neoplasms genetics   metabolism   MeSH
• Paraganglioma genetics   metabolism   MeSH
• Succinate Dehydrogenase genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Research Support, N.I.H., Intramural MeSH
• Names of Substances
• Succinate Dehydrogenase MeSH

Drug repurposing or repositioning is an important part of drug discovery that has been growing in the last few years for the development of therapeutic options in oncology. We applied this paradigm in a screening of a library of about 3,800 compounds (including FDA-approved drugs and pharmacologically active compounds) employing a model of metastatic pheochromocytoma, the most common tumor of the adrenal medulla in children and adults. The collection of approved drugs was screened in quantitative mode, testing the compounds in compound-titration series (dose-response curves). Analysis of the dose-response screening data facilitated the selection of 50 molecules with potential bioactivity in pheochromocytoma cells. These drugs were classified based on molecular/cellular targets and signaling pathways affected, and selected drugs were further validated in a proliferation assay and by flow cytometric cell death analysis. Using meta-analysis information from molecular targets of the top drugs identified by our screening with gene expression data from human and murine microarrays, we identified potential drugs to be used as single drugs or in combination. An example of a combination with a synergistic effect is presented. Our study exemplifies a promising model to identify potential drugs from a group of clinically approved compounds that can more rapidly be implemented into clinical trials in patients with metastatic pheochromocytoma or paraganglioma.

• MeSH
• Adult MeSH
• Pheochromocytoma drug therapy   genetics   secondary   MeSH
• Real-Time Polymerase Chain Reaction MeSH
• Humans MeSH
• RNA, Messenger genetics   MeSH
• Mice MeSH
• Biomarkers, Tumor genetics   metabolism   MeSH
• Adrenal Gland Neoplasms drug therapy   genetics   pathology   MeSH
• Drug Discovery * MeSH
• Paraganglioma drug therapy   genetics   pathology   MeSH
• Reverse Transcriptase Polymerase Chain Reaction MeSH
• Drug Repositioning * MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents pharmacology   MeSH
• Flow Cytometry MeSH
• High-Throughput Screening Assays * MeSH
• Oligonucleotide Array Sequence Analysis MeSH
• Signal Transduction MeSH
• Gene Expression Profiling MeSH
• Blotting, Western MeSH
• Animals MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, N.I.H., Intramural MeSH
• Names of Substances
• RNA, Messenger MeSH
• Biomarkers, Tumor MeSH
• Antineoplastic Agents MeSH