Diagnosis, Pathophysiology And Molecular Biology of Pheochromocytoma and Paraganglioma

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The Section is conducting patient-oriented research about the etiology, epidemiology, pathophysiology, genetics, diagnosis, and treatment of pheochromocytoma and paraganglioma (PPGL). Projects include not only translational research-applying basic science knowledge to clinical diagnosis, pathophysiology, and treatment-but also reverse translation research where appreciation of clinical findings leads to new concepts that basic researchers can pursue in the laboratory. In order to achieve our goals, the strategy of the Section is based on the multidisciplinary collaborations among NIH investigators and outside medical centers/institutions. Our Section links together a patient-oriented component with two bench-level components. The patient-oriented component (Medical Neuroendocrinology) is currently the main driving force for our hypotheses and discoveries. The two bench-level components (Tumor Pathogenesis, Genetics, Chemistry & Biomarkers and Experimental Immunotherapies) emphasize first, technologies of basic research tailored for pathway and target discovery and second, the development of the discoveries into clinical applications. Clinical and genetic aspects of PPGLs PPGLs are rare in children with only a few SDHB mutation-related cases. Previous studies on children were conducted in small cohorts. This large set of pediatric patients provides robust data in the evaluation of clinical outcomes. Thirty-eight males and 26 females were diagnosed with PPGL at a median age of 13 years. The majority of patients displayed norepinephrine hypersecretion and 73.44% initially presented with a solitary tumor. Metastases developed in 70% of patients at the median age of 16 years and were mostly diagnosed first 2 years and in years 12-18 post-diagnosis. The presence of metastases at the time of diagnosis had a strong negative impact on survival in males but not in females. The estimated 5-, 10-, and 20-year survival rates were 100%, 97.14%, and 77.71%, respectively. The present report has highlighted several important aspects in the management of pediatric patients with SDHB mutations associated-PHEO/PGL. Initial diagnostic evaluation of SDHB mutation carriers should be started at age of 5-6 years with initial work-up focusing on abdominal region. Thorough follow-up is crucial first 2 years post-diagnosis and more frequent follow-ups are needed in years 10-20 post-diagnosis due to the increased risk of metastases. Although this age group developed metastasis as early as 5 years from diagnosis, we have shown that the overall 20-year prognosis and survival are good. A PPGL-related clinical sequela results from catecholamine secretion that can cause hypertension, tachyarrhythmia, multiorgan failure, and death caused by elevated catecholamine levels. We have introduced Ivabradine is a commercially available drug that acts directly in the sinus node in the heart for treatment of severe catecholamine-induced tachyarrhythmia. We also published some comprehensive reviews on cardia PGLs as well as treatments of arrhythmias. In another study we evaluated PPGL patients with SDHA gene mutation. Our findings suggest that these tumors can occur early and at extra-adrenal locations, behave aggressively, and have a tendency to develop metastatic disease within a short period of time. None of our patients had a family history of PPGL, making them appear sporadic. Nine out of 10 patients showed abnormal PPGL-specific biochemical markers with predominantly noradrenergic and/or dopaminergic phenotype, suggesting their utility in diagnosing and monitoring the disease. 68Ga-DOTATATE PET was superior to other imaging modalities in the localization of these tumors. All 7 out of 7 patients who received conventional therapies (chemotherapy, somatostatin analog therapy, radiation therapy, 131I-MIBG, peptide receptor radionuclide therapy) in addition to surgery showed progression. Imaging aspects of PPGLs Diverse radionuclide imaging techniques are available for the diagnosis, staging, and follow-up of PPGL. Beyond their ability to detect and localise the disease, these imaging approaches variably characterize these tumors at the cellular and molecular levels and can guide therapy. We updated guidelines jointly approved by the EANM and SNMMI for assisting nuclear medicine practitioners in not only the selection and performance of currently available single-photon emission computed tomography and positron emission tomography procedures, but also the interpretation and reporting of the results from PPGL patients. We also published the review about molecular imaging and radionuclide therapy of PPGL in the era of genomic characterization. Metabolic aspects of PPGLs Brown adipose tissue (BAT) activation is mediated through the action of norepinephrine on -adrenoceptors (-ARs). In some malignancies, BAT activation is associated with higher cancer activity. A retrospective case-control study that included 342 patients with PPGLs who underwent 18F-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography (18F-FDG PET/CT) imaging at the National Institutes of Health (NIH). The presence of active BAT on 18F-FDG PET/CT was associated with decreased overall survival when compared with the control group. This association remained significant after adjusting for the SDHB mutation. Median plasma norepinephrine in the BAT group was higher than the control group. There was a significant association between higher plasma norepinephrine levels and mortality in PPGLs in both groups. Therapeutic aspects of PPGLs: PPGLs are usually benign neuroendocrine tumors. However, PPGLs with mutations in the succinate dehydrogenase B subunit (SDHB) have a poor prognosis and frequently develop metastatic lesions. SDHB-mutated PPGLs exhibit dysregulation in oxygen metabolic pathways, including pseudohypoxia and formation of reactive oxygen species, suggesting that targeting the redox balance pathway could be a potential therapeutic approach. By investigating PPGLs cells with low SDHB levels, we show that pseudohypoxia resulted in elevated expression of iron transport proteins, including transferrin (TF), transferrin receptor 2 (TFR2), and the divalent metal transporter 1 (SLC11A2; DMT1), leading to iron accumulation. This iron overload contributed to elevated oxidative stress. Ascorbic acid (vitamin C) at pharmacologic concentrations disrupted redox homeostasis, inducing DNA oxidative damage and cell apoptosis in PPGL cells with low SDHB levels. Moreover, through a preclinical animal model with PPGL allografts, we demonstrated that pharmacologic ascorbic acid suppressed SDHB-low metastatic lesions and prolonged overall survival. The data here demonstrate that targeting redox homeostasis as a cancer vulnerability with pharmacologic ascorbic acid is a promising therapeutic strategy for SDHB-mutated PPGLs. Mechanistically, nuclear factor erythroid 2-related factor 2 (NRF2)-guided glutathione de novo synthesis plays a key role in supporting cellular survival and the proliferation of SDHB-knockdown cells We found that NRF2 blockade not only disrupted reactive oxygen species homeostasis in SDHB-deficient cells but also caused severe cytotoxicity by the accumulation of DNA oxidative damage. Brusatol, a potent NRF2 inhibitor, showed a promising effect in suppressing SDHB gene suppressed metastatic lesions in vivo, with prolonged overall survival in mice bearing PPGLs allografts. Our findings highlight a novel therapeutic strategy of targeting the NRF2-driven glutathione metabolic pathway against SDHB-mutated PPGLs. As the member of the Working group on Endocrine Hypertension of the European Society of Hypertension, we outlined newest approaches to evaluation and treatment of a patient with PPGLs based on current knowledge in PPGL epidemiology, genetics, diagnosis, treatme