Dataset Information

High-throughput screening for the identification of new therapeutic options for metastatic pheochromocytoma and paraganglioma.

ABSTRACT: 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.

SUBMITTER: Giubellino A

PROVIDER: S-EPMC3974653 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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High-throughput screening for the identification of new therapeutic options for metastatic pheochromocytoma and paraganglioma.

Giubellino Alessio A Shankavaram Uma U Bullova Petra P Schovanek Jan J Zhang Yaqin Y Shen Min M Patel Nikita N Elkahloun Abdel A Lee Min-Jung MJ Trepel Jane J Ferrer Marc M Pacak Karel K

PloS one 20140403 4

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 quantitativ ...[more]

PMID: 24699253

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Project description:Although pediatric pheochromocytomas and paragangliomas (PPGLs) are rare, they have important differences compared to those in adults. Unfortunately, without timely diagnosis and management, these tumors have a potentially devastating impact on pediatric patients. Pediatric PPGLs are more often extra-adrenal, multifocal/metastatic, and recurrent, likely due to these tumors being more commonly due to a genetic predisposition than in adults. This genetic risk results in disease manifestations at an earlier age giving these tumors time to advance before detection. In spite of these problematic features, advances in the molecular and biochemical characterization of PPGLs have heralded an age of increasingly personalized medicine. An understanding of the genetic basis for an individual patient's tumor provides insight into its natural history and can guide clinicians in management of this challenging disease. In pediatric PPGLs, mutations in genes related to pseudohypoxia are most commonly seen, including the von Hippel-Lindau gene (VHL) and succinate dehydrogenase subunit (SDHx) genes, with the highest risk for metastatic disease associated with variants in SDHB and SDHA. Such pathogenic variants are associated with a noradrenergic biochemical phenotype with resultant sustained catecholamine release and therefore persistent symptoms. This is in contrast to paroxysmal symptoms (e.g., episodic hypertension, palpitations, and diaphoresis/flushing) as seen in the adrenergic, or epinephrine-predominant, biochemical phenotype (due to episodic catecholamine release) that is commonly observed in adults. Additionally, PPGLs in children more often present with signs and symptoms of catecholamine excess. Therefore, children, adolescents, and young adults present differently from older adults (e.g., the prototypical presentation of palpitations, perspiration, and pounding headaches in the setting of an isolated adrenal mass). These presentations are a direct result of genetic determinants and highlight the need for pediatricians to recognize these differences in order to expedite appropriate evaluations, including genetic testing. Identification and familiarity with causative genes inform surveillance and treatment strategies to improve outcomes in pediatric patients with PPGL.

Project description:Context: Metastatic pheochromocytoma/paraganglioma (MPP) therapy mainly involves radionuclide therapy, chemotherapy, and targeted therapy. In recent years, temozolomide (TMZ) showed great promise in some MMP patients, especially those with SDHB germline mutation. We reported a patient with MPP who did not have any known germline genetic change and responded remarkably well to TMZ monotherapy. Case presentation: The patient was a 41-year-old woman with local and distant recurrence (soft tissues and bone metastases) of retroperitoneal paraganglioma. She suffered from dizziness, palpitation, sweating, weight loss and constipation, with the blood pressure fluctuating substantially from 130/100 mmHg to 190/120 mmHg, although she was on phenoxybenzamine and metoprolol medication. The patient showed clinical and radiological response after 3-cycle TMZ therapy. Upon 15 cycles of TMZ therapy, her symptoms were dramatically alleviated, urinary norepinephrine excretion decreased from 1,840 μg/24 h to 206 μg/24 h, and CT showed that the lesions further shrank. Molecular profiling of the tumor tissue of the patient revealed hypermethylation of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter and a negative immunostaining for MGMT. Globally, only 26 cases of MPP treated with TMZ have been described so far. TMZ is effective, especially in patients with SDHB mutation, which can be explained by the silencing of MGMT expression as a consequence of MGMT promoter hypermethylation in SDHB-mutated tumors. Although, in general, patients with SDHB mutation or MGMT promoter hypermethylation have better response to TMZ, there are also exceptions. Severe side effects are uncommon, with only 17.4% patients experiencing Grade 3 toxicities, including lymphopenia, and hypertension. Conclusions: TMZ is effective and safe in MPP patients, and, it may work better on patients with SDHB-related MPP. Measurement of MGMT expression might help assess the tumor sensitivity to TMZ but this needs further systematic investigation.

Dataset Information

High-throughput screening for the identification of new therapeutic options for metastatic pheochromocytoma and paraganglioma.

Publications

High-throughput screening for the identification of new therapeutic options for metastatic pheochromocytoma and paraganglioma.

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