The Section is conducting patient-oriented research about the etiology, epidemiology, pathophysiology, genetics, diagnosis, and treatment of pheochromocytoma (PHEO) and paraganglioma (PGL). 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 Succinate dehydrogenase subunit B (SDHB) gene mutations are associated with an aggressive clinical disease course of pheochromocytoma/paraganglioma (PPGL). Limited information is available concerning PPGL penetrance among SDHB mutation carriers with regards to primary tumor location, specific mutation type, and gender. We assessed PPGL penetrance in SDHB mutation carriers and described the clinical presentation and disease course. Asymptomatic relatives (N=611) of 103 index patients were tested for SDHB mutations. Forty (16.60%) of the 241 screened individuals developed PPGL during the study. The penetrance estimate in this population was 49.80% (95% CI 29-74.9) at 85 years. A significantly higher age-related penetrance of disease was observed in males compared to females, with 50% penetrance achieved at age 74 vs. not reached. Age-related penetrance analysis demonstrated 4 mutations (Ile127Ser, IVS1+1G>T, Exon 1 deletion, Arg90X) presenting with a slower rate of disease development (50% penetrance ages, respectively: not achieved, 70, 63, 61 years) compared to Arg46X and Val140Phe mutations (50% penetrance at 38 years). Thus, we found a higher estimated penetrance compared to several other studies, and a striking difference in age-related penetrance between male and female SDHB mutation carriers with no association between mutation and gender or tumor location Children with PPGLs showed higher (P < 0.0001) prevalence than adults of hereditary (80.4% vs 52.6%), extra-adrenal (66.3% vs 35.1%), multifocal (32.6% vs 13.5%), metastatic (49.5% vs 29.1%), and recurrent (29.5% vs 14.2%) PPGLs. Tumors due to cluster 1 mutations were more prevalent among children than adults (76.1% vs 39.3%; P < 0.0001), and this paralleled a higher prevalence of noradrenergic tumors, characterized by relative lack of increased plasma metanephrine, in children than in adults (93.2% vs 57.3%; P < 0.0001). . Imaging aspects of PPGLs To evaluate and compare diagnostic performance of 68Ga-DOTA(0)-Tyr(3)-octreotate (68Ga-DOTATATE) with 18F-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography-computed tomography (PET/CT) and anatomic imaging using computed tomography and/or magnetic resonance (CT/MR) imaging in detection of SDHx-related PPGLs in pediatric patients. Our preliminary study demonstrates the superiority of 68Ga-DOTATATE PET/CT in localization of SDHx-related PPGLs in pediatric population compared to 18F-FDG PET/CT and CT/MR imaging with the exception of abdominal (excluding adrenal and liver) lesions, and suggests that it might be considered as a first-line imaging modality in pediatric patients with SDHx-related PPGLs. Metabolic aspects of PPGLs Glucose is metabolized via glycolysis to generate pyruvate that undergoes mitochondrial oxidation by the tricarboxylic acid (TCA) cycle. Cellular energy status (i.e., ATP levels) is maintained primarily through the electron transport chain and oxidative phosphorylation. SDHx-related mutated cells are characterized by decreased SDH activity with TCA blockade, and the accumulation of highly elevated concentrations of succinate. Succinate can act both as an intracellular and an extracellular messenger. Succinate leads to a set of distinct features via HIF protein stabilization, despite normal oxygen supply (pseudohypoxia), leading to increased expression of HIF target genes (angiogenesis, proliferation, metabolic adaptation) and DNA hypermethylation (dedifferentiation, epithelial to mesenchymal transition). For the first time we showed that succinate promotes angiogenesis and activate 18F-FDG uptake by endothelial cells Therapeutic aspects of PPGLs We found that cluster I PPGLs 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 PPGLs 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 PPGL allograft.Conclusions: In summary, our findings provide novel insights into an effective strategy for targeting cluster I PCPGs, especially those with SDHB mutations. Cyclophosphamide-dacarbazine-vincristine (CVD) regimen is recommended as standard chemotherapy for advanced metastatic PPGL. We report 2 patients with SDHB-related metastatic PGL who received a regimen consisting of metronomic scheme temozolomide (TMZ) and high-dose lanreotide after progression on both CVD chemotherapy and high-dose lanreotide. Molecular profiling of the tumor tissue from both patients revealed hypermethylation of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter. In one patient, progression-free survival was 13months and the second patient remained under treatment after 27months of stabilization of metabolic response of his disease. Treatment was well tolerated, and adverse effects were virtually absent. A modification in the scheme of TMZ from standard schemes to MS is safe and feasible and can be considered in patients with progressive metastatic PPGL refractory to dacarbazine in standard doses Together with NCI we opened a new protocol focusing on radiotherapy of metastatic or inoperable PPGL using 177Lu-DOTATATE (Lutathera). The protocol is focusing on repeated radiotherapy in these patients and their very careful follow up. The protocol is open for recruiting.
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