RARE DISEASE
Hereditary pheochromocytoma-paraganglioma
Hereditary pheochromocytoma-paraganglioma
Hereditary pheochromocytoma-paraganglioma
Synonyms: Familial pheochromocytoma-paraganglioma
Synonyms: Familial pheochromocytoma-paraganglioma
Synonyms: Familial pheochromocytoma-paraganglioma
Drug discovery
1
drug
With orphan designation
Overview
Hereditary pheochromocytoma-paraganglioma (PPGL) syndromes are autosomal dominant disorders caused by germline mutations in SDHx, MAX, TMEM127, or other genes. These neuroendocrine tumors arise from chromaffin cells, with pheochromocytomas localized to adrenal glands and paragangliomas occurring in sympathetic/parasympathetic ganglia. Approximately 30-40% of PPGL cases are hereditary [2][12][15], often presenting with catecholamine excess (hypertension, palpitations) or mass effects. Metastasis risk varies by gene (e.g., 25-50% with SDHB mutations) [1][12], and associated tumors include gastrointestinal stromal tumors (GISTs) and renal cell carcinoma [1][5].
Therapies
Surgical resection (first-line), preceded by α/β-blockade for secretory tumors [1][7][10]
Metastatic disease: Tyrosine kinase inhibitors (sunitinib, cabozantinib), chemotherapy (cyclophosphamide/dacarbazine), and (^{131})I-MIBG radionuclide therapy [3][7][17]
Surveillance: Lifelong biochemical testing (metanephrines) and imaging (MRI/CT) for recurrence [6][8][10]
Categories: rare endocrine diseases, rare genetic diseases, rare neoplastic diseases
Research Papers
391 drug discovery papers about Hereditary pheochromocytoma-paraganglioma, with 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
391 drug discovery papers about Hereditary pheochromocytoma-paraganglioma, with 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-30 | Fluctuating hypertension possibly leading to severe cardiomyopathy in SDHB-associated hereditary paraganglioma: from heart transplant candidacy to long-term lanreotide management: a case report
Introduction: Paragangliomas are rare catecholamine-secreting neuroendocrine tumors that can cause significant cardiovascular complications, including catecholamine-induced cardiomyopathy. While surgical resection is the standard of care, some patients are not candidates for surgery or heart transplantation due to tumor biology, genetic risk, or patient preference. Case summary: A 68-year-old man with longstanding hypertension, hereditary paraganglioma-pheochromocytoma syndrome (SDHB mutation), and advanced nonischemic cardiomyopathy was evaluated for heart transplantation. Imaging revealed a highly vascular retroperitoneal paraganglioma, and biochemical testing demonstrated markedly elevated chromogranin A with mildly increased plasma free normetanephrine. Biopsy confirmed paraganglioma. Due to transplant ineligibility related to malignancy risk and the patient's decision to decline surgical resection, medical therapy with lanreotide was initiated. Following treatment, the patient demonstrated biochemical improvement with declining chromogranin A levels, stabilization of blood pressure, improvement in B-type natriuretic peptide, modest recovery of left ventricular ejection fraction, and reduced metabolic activity on serial somatostatin receptor PET/CT imaging, with stable tumor size. Functional status remained excellent without further heart failure hospitalizations. Conclusion: This case highlights lanreotide as a potential non-surgical therapeutic option for paraganglioma-associated cardiomyopathy in select high-risk patients. Systemic tumor control may contribute to cardiovascular stabilization when surgical or transplant options are not feasible.
2026-07-28 | Clinical Impact of Germline Multigene Sequencing in Pediatric Cohorts with a Wide Spectrum of Neoplasms.
Cancer predisposition syndromes (CPSs) account for 8.5-18% of all childhood cancer cases. Most of them are inherited in an autosomal dominant pattern; consequently, there is a 50% risk of transmission to offspring. Early detection of CPSs is crucial for choosing patient treatment strategies and for counseling in the family. This study enrolled 886 pediatric patients with hematologic and solid neoplasms from prospective and retrospective cohorts (2018-2025). Clinical exome or multigene panel sequencing was used to analyze blood DNA. Overall, 186 pathogenic/likely pathogenic (PLP) variants in cancer-associated genes were identified in 176/886 (20%) of patients, and the most frequently mutated were the NF1 (n = 35) and TP53 (n = 18) genes. Among the 186 PLP variants, 126/886 (14.2%) were causative for pediatric neoplasms, while 56/886 (6.3%) were heterozygous mutations associated with adult-onset CPSs affecting DNA repair. The highest total mutation rate was revealed in retinoblastoma (80%), peripheral nerve sheath tumors (60%), and pheochromocytoma/paraganglioma (47%), while the lowest rate was found in hematologic malignancies (4.6%) and neuroblastoma (12%). The wide range and high frequency of deleterious variants in pediatric patients, especially in those with solid tumors, highlights the importance of multigene panel sequencing for the accurate determination of CPSs.
2026-07-22 | A multistakeholder call for belzutifan biomarker data in advanced pheochromocytoma and paraganglioma.
The HIF-2α inhibitor belzutifan was recently U.S. Food and Drug Administration (FDA)-approved for advanced pheochromocytoma/paraganglioma. This multistakeholder article calls for clinical-trial genomic correlates and outcome data to clarify efficacy across these molecularly heterogeneous neuroendocrine tumors.
2026-02-19 | Succinate dehydrogenase-deficient cancer cells have increased susceptibility to Ym155-induced DNA damage
The hereditary pheochromocytoma and paraganglioma (hPPGL) syndrome, caused by germline mutations in succinate dehydrogenase (SDHx) genes, predisposes individuals to pheochromocytomas (Pheo), paragangliomas (PGLs), renal cell carcinoma (RCC) and gastrointestinal stromal tumors (GISTs). Notably, tumors with succinate dehydrogenase subunit B (SDHB) deficiency demonstrate an increased metastatic risk and current systemic treatments remain only palliative. Hence, discovering novel therapeutic avenues to improve SDHB cancer prognosis is an urgent need. Here, we leveraged human SDHB-deficient UOK269 RCC cells (SDHB-KO) and isogenic SDHB-reconstituted control cells (SDHB-WT) to discover SDH-dependent mitochondria-directed cytotoxic agents. Given the reduced ATP-generating capacity of SDHB-KO cells, we hypothesized that they would be uniquely sensitive to futile cycle induction with mitochondrial ionophores. Indeed, ionophores exhibited preferential cytotoxicity toward SDHB-KO cells. However, the mitochondria-directed chemotherapeutic compound Ym155 demonstrated more potent and dramatic preferential cytotoxicity toward SDHB-KO cells. Importantly, SDH-dependent cytotoxicity of Ym155 was validated in multiple cell models, including primary human pheochromocytoma cells, a mouse pheochromocytoma (MPC) cell line and primary SDHB-deficient mouse kidney cells. Notably, genetic evidence of Ym155 synthetic lethality with SDHB deficiency was buttressed in additional cell models using two chemical inhibitors of SDH enzyme activity. Mechanistically, SDH deficiency sensitized cells to Ym155-induced DNA damage. Strikingly, SDH-dependent Ym155 sensitivity was recapitulated by inhibition of the histone demethylase KDM4, a downstream consequence of SDH deficiency. In summary, accumulation of succinate in SDH-deficient tumors inhibited KDM4 activity, impaired DNA repair and yielded enhanced susceptibility to Ym155-induced reactive oxygen species (ROS) generation. The identified intrinsic susceptibilities of SDHB-deficient cancers have the potential to be therapeutically leveraged.
2026-02-03 | Targeting HIF-2α in renal cell carcinoma: Expanding upon belzutifan.
Clear cell renal cell carcinoma (ccRCC) is a common subtype of kidney cancer driven by the inactivation of the von Hippel-Lindau (VHL) gene, leading to the accumulation of hypoxia-inducible factor (HIF)-2α and tumorigenesis. Targeting HIF-2α has emerged as a promising therapeutic strategy culminating in the development of a first-in-class inhibitor, belzutifan, invented by Peloton Therapeutics and marketed by Merck. This article presents the journey to belzutifan and subsequent developments. We discuss the structure-based design leading to the first-in-human drug, PT2385, as well as subsequent modifications to improve pharmacokinetic properties leading to PT2977/belzutifan. Detailed analyses are presented of key HIF-2α structural features, the mechanism of drug action, and how this family of drugs performed in preclinical models. Belzutifan's impact on patients with VHL syndrome, sporadic advanced ccRCC and pheochromocytoma/paraganglioma is discussed, three areas where belzutifan has obtained Food and Drug Administration approval. Drug combination strategies, mechanisms of resistance, and emerging strategies to overcome them, including siRNA-based therapeutics, are presented. Alternative HIF-2α inhibitors are examined, including NKT2152 and AB521. By expanding upon the foundation established by belzutifan, the field is poised for further therapeutic advances.
gene therapies
2025-12-24 | Precision Care for Hereditary Urologic Cancers: Genetic Testing, Counseling, Surveillance, and Therapeutic Implications.
Hereditary predisposition substantially shapes prevention and management across urologic oncology. This narrative review synthesizes contemporary, practice-oriented guidance on whom to test, what to test, how to act on results, and how to implement care equitably for hereditary forms of prostate cancer, renal cell carcinoma (RCC), urothelial carcinoma, pheochromocytoma/paraganglioma (PPGL), and adrenocortical carcinoma (ACC). We delineate between forms of indication-driven germline testing (e.g., universal testing in metastatic prostate cancer; early-onset, bilateral/multifocal, or syndromic RCC; reflex tumor mismatch repair (MMR)/microsatellite instability (MSI) screening in upper-tract urothelial carcinoma (UTUC); universal testing in PPGL; universal TP53 testing in ACC) and pair these strategies with minimum actionable gene sets and syndrome-specific surveillance frameworks. Key points include targeted prostate-specific antigen screening in BRCA2 carriers and the impact of BRCA/ATM variants on reclassification during active surveillance; major hereditary RCC syndromes with genotype-tailored surveillance and pathway-directed therapy (e.g., HIF-2α inhibition for von Hippel-Lindau disease); UTUC/bladder cancer in Lynch syndrome with tumor MMR/MSI screening, annual urinalysis (selective cytology), and immunotherapy opportunities in deficient MMR disease/MSI-H; PPGL management emphasizing universal germline testing, intensified surveillance for SDHB, cortical-sparing adrenalectomy, and emerging HIF-2α inhibition; and ACC care modified by Li-Fraumeni syndrome (minimization of radiation/genotoxic therapy with whole-body imaging surveillance). Testicular germ cell tumor remains largely polygenic, with no routine germline testing in typical presentations. Finally, we provide pre-/post-test genetic-counseling checklists and mainstreamed workflows with equity metrics to operationalize precision care and close real-world access gaps.
2019-05-23 | 65 YEARS OF THE DOUBLE HELIX: Genetics informs precision practice in the diagnosis and management of pheochromocytoma.
Although the authors of the present review have contributed to genetic discoveries in the field of pheochromocytoma research, we can legitimately ask whether these advances have led to improvements in the diagnosis and management of patients with pheochromocytoma. The answer to this question is an emphatic Yes! In the field of molecular genetics, the well-established axiom that familial (genetic) pheochromocytoma represents 10% of all cases has been overturned, with >35% of cases now attributable to germline disease-causing mutations. Furthermore, genetic pheochromocytoma can now be grouped into five different clinical presentation types in the context of the ten known susceptibility genes for pheochromocytoma-associated syndromes. We now have the tools to diagnose patients with genetic pheochromocytoma, identify germline mutation carriers and to offer gene-informed medical management including enhanced surveillance and prevention. Clinically, we now treat an entire family of tumors of the paraganglia, with the exact phenotype varying by specific gene. In terms of detection and classification, simultaneous advances in biochemical detection and imaging localization have taken place, and the histopathology of the paraganglioma tumor family has been revised by immunohistochemical-genetic classification by gene-specific antibody immunohistochemistry. Treatment options have also been substantially enriched by the application of minimally invasive and adrenal-sparing surgery. Finally and most importantly, it is now widely recognized that patients with genetic pheochromocytoma/paraganglioma syndromes should be treated in specialized centers dedicated to the diagnosis, treatment and surveillance of this rare neoplasm.
2018-08-19 | Whole Exome Sequencing Uncovers Germline Variants of Cancer-Related Genes in Sporadic Pheochromocytoma
Pheochromocytomas (PCCs) show the highest degree of heritability in human neoplasms. However, despite the wide number of alterations until now reported in PCCs, it is likely that other susceptibility genes remain still unknown, especially for those PCCs not clearly syndromic.Whole exome sequencing of tumor DNA was performed on a set of twelve PCCs clinically defined as sporadic.About 50% of PCCs examined had somatic mutations on the known susceptibility VHL, NF1, and RET genes. In addition to these driver events, mutations on SYNE1, ABCC10, and RAD54B genes were also detected. Moreover, extremely rare germline variants were present in half of the sporadic PCC samples analyzed, in particular variants of MAX and SAMD9L were detected in the germline of cases wild-type for mutations in the known susceptibility genes.Additional somatic passenger mutations can be associated with known susceptibility VHL, NF1, and RET genes in PCCs, and a wide number of germline variants with still unknown clinical significance can be detected in these patients. Therefore, many efforts should be aimed to better define the pathogenetic role of all these germline variants for discovering novel potential therapeutic targets for this disease still orphan of effective treatments.
2014-03-27 | Opposing effects of HIF1α and HIF2α on chromaffin cell phenotypic features and tumor cell proliferation: Insights from MYC‐associated factor X
Pheochromocytomas and paragangliomas (PPGLs) are catecholamine‐producing chromaffin cell tumors with diverse phenotypic features reflecting mutations in numerous genes, including MYC‐associated factor X ( MAX ). To explore whether phenotypic differences among PPGLs reflect a MAX‐mediated mechanism and opposing influences of hypoxia‐inducible factor (HIF)s HIF2α and HIF1α, we combined observational investigations in PPGLs and gene‐manipulation studies in two pheochromocytoma cell lines. Among PPGLs from 140 patients, tumors due to MAX mutations were characterized by gene expression profiles and intermediate phenotypic features that distinguished these tumors from other PPGLs, all of which fell into two expression clusters: one cluster with low expression of HIF2α and mature phenotypic features and the other with high expression of HIF2α and immature phenotypic features due to mutations stabilizing HIFs. Max ‐mutated tumors distributed to a distinct subcluster of the former group. In cell lines lacking Max , re‐expression of the gene resulted in maturation of phenotypic features and decreased cell cycle progression. In cell lines lacking Hif2α , overexpression of the gene led to immature phenotypic features, failure of dexamethasone to induce differentiation and increased proliferation. HIF1α had opposing actions to HIF2α in both cell lines, supporting evolving evidence of their differential actions on tumorigenic processes via a MYC/MAX‐related pathway. Requirement of a fully functional MYC/MAX complex to facilitate differentiation explains the intermediate phenotypic features in tumors due to MAX mutations. Overexpression of HIF2α in chromaffin cell tumors due to mutations affecting HIF stabilization explains their proliferative features and why the tumors fail to differentiate even when exposed locally to adrenal steroids.
2011-12-01 | Is genetic screening indicated in apparently sporadic pheochromocytomas and paragangliomas?
Pheochromocytoma (Pheo) is usually considered a sporadic disease. Recently, an increasing rate of genetically based tumors has been reported. However, the need for systematic screening of unsuspected germline mutations in apparently sporadic forms is still debated. This study aimed to assess the effective rate of germline mutations causing Pheo and Paraganglioma (PGL), and the role of systematic genetic screening.Demographics, clinical, and genetic evaluation were performed in a series of 71 patients with Pheo and/or PGL.Twelve patients had evident inherited/familial disease at presentation: NF1 (n = 4); MEN2 (n = 4), and familial Pheo/PGL (n = 4). Among 59 patients with apparently sporadic disease, unsuspected germline mutations occurred in 8 cases: TMEM127 (n = 4), SDHB (n = 2), VHL (n = 1), SDHC (n = 1). No differences were found between hereditary and sporadic disease concerning age, sex, and tumor size; bilateral Pheo and/or PGL and recurrences occurred most often in hereditary disease.Hereditary Pheo and/or PGL are frequent (28.2%). Inheritance is evident at presentation only in 16.9% of cases; 13.6% of apparently sporadic variants are genetically determined. Despite increased costs, systematic genetic screening might be useful because it might lead to a stricter follow-up, early diagnosis of recurrences in index cases and presymptomatic detection of disease in relatives.
proteins
2024-04-15 | PD23-02 IMPACT OF TRAP1 ON COMPLEX II ASSEMBLY IN CELLS WITH PATHOGENIC FAMILIAL PHEOCHROMOCYTOMA ASSOCIATED MUTATIONS
You have accessJournal of UrologyAdrenal (PD23)1 May 2024PD23-02 IMPACT OF TRAP1 ON COMPLEX II ASSEMBLY IN CELLS WITH PATHOGENIC FAMILIAL PHEOCHROMOCYTOMA ASSOCIATED MUTATIONS Nathan Nahhas and Mark R. Woodford Nathan NahhasNathan Nahhas and Mark R. WoodfordMark R. Woodford View All Author Informationhttps://doi.org/10.1097/01.JU.0001008664.51020.58.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The succinate dehydrogenase enzyme (SDH) is integral to the oxidative phosphorylation pathway, and has been found to play a role in tumor oncogenesis and metabolism. SDH loss of function mutations are associated with pheochromocytomas and paragangliomas. Germline mutations have also been associated with familial tumor syndromes. No targeted pharmaceutical therapies are available for these tumors. The mitochondrial chaperone TNF-receptor associated protein 1 (TRAP1) and SDHAF2 assembly factor have been shown to participate in SDH complex assembly, but their functional pathway is not fully elucidated. TRAP1 expression is upregulated in multiple cancer models, and previous work has shown that inhibition of TRAP1 induces apoptosis in tumor cells. The objective of our work was to determine the mechanism of uncharacterized pathogenic SDH and SDHAF2 mutations and what role TRAP1 plays in this process. METHODS: DNA plasmid transfection of mutants clinically associated with pheochromocytoma in 293 wild type and SDHB subunit knock out cells was used to modulate levels of SDHB and SDHAF2 proteins. Immunoblotting and immunoprecipitation were used with submitochondrial fractionation to evaluate protein expression and interaction in the setting of TRAP1 drug inhibition. In vitro enzymatic assays and real-time respiratory assays were used to evaluate SDH activity. RESULTS: SDHB mutation resulted in impaired binding to the SDHA subunit and failed to rescue respiratory function compared to wild type. The pathogenic SDHAF2-G78R mutant also exhibited reduced binding to SDHA and decreased SDH activity in vitro. Interestingly, we were not able to observe interaction between TRAP1 and SDHAF2. Further, TRAP1 knockout compromised binding between SDHAF2 and SDHA. This indicated that TRAP1 is unable to incorporate pathogenic mutant proteins into functional SDH complexes. CONCLUSIONS: TRAP1 has a regulatory role in assembly of functional SDH complexes, and TRAP1 binding has been shown to inhibit the function of SDH. However, TRAP1 fails to bind with pathogenic mutations of SDHB, leading to a lack of respiratory function. In both TRAP1 knockout and pathogenic SDHAF2 mutations, SDH complexes fail to assemble, suggesting that TRAP1 and SDHAF2 are both required for SDH complex function. Our data suggests TRAP1 and SDHAF2 act in a mutually exclusive manner for SDH complex assembly. As TRAP1 regulates respiratory function, TRAP1 modification therapy could be explored for patients with familial pheochromocytoma syndrome or tumors with metabolic SDH dysregulation. Source of Funding: Upstate Medical University Department of Urology,Upstate Medical University Department of Biochemistry & Molecular Biology, Upstate Cancer Center at SUNY Upstate Medical University © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e523 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Nathan Nahhas More articles by this author Mark R. Woodford More articles by this author Expand All Advertisement PDF downloadLoading ...
2023-07-01 | Unusual case report of malignant pheochromocytoma presenting with STEMI
Pheochromocytomas (PHEOs) are a group of tumours that leads to multiple symptoms and can induce hypercoagulability and promote thrombosis. Pheochromocytomas may also present without elevated serum and urinary markers. We aimed to provide tips and tricks for the diagnostic and therapeutic management of an unusual case of PHEOs.Thirty-four-year-old woman with the unremarkable medical history presented with epigastric pain and dyspnoea. Electrocardiogram showed ST-segment elevation in the inferior limb leads. She underwent an emergency coronary angiogram, which showed a high thrombus burden in the distal right coronary artery. A subsequent echocardiogram demonstrated a 31 × 33 mm right atrial mass adhering to the inferior vena cava and abdominal computed tomography (CT) scan revealed a 113 × 85 mm necrotic mass in the left adrenal bed, with tumour thrombus extending proximally to the confluence of hepatic veins immediately inferior to the right atrium and distally to iliac vein bifurcation. Blood parameters, thrombophilia panel, vanillylmandelic acid, 5 hydroxy indole acetic acid, and homovanillic acid levels were normal. Tissue sampling confirmed the diagnosis of PHEOs. The surgical procedure was not planned due to the presence of metastatic foci on imaging, including positron emission tomography (PET)-CT. Anticoagulation with rivaroxaban and treatment with 177Lu-DOTATATE-based peptide receptor radionuclide therapy (PRRT) was initiated.The coexistence of arterial and venous thrombosis is extremely rare in patients with PHEOs. Multidisciplinary approaches are required for the care of such patients. Catecholamines likely contributed to the development of thrombosis in our patient. Early recognition of PHEOs is the key point to ameliorate clinical outcomes.
2022-02-07 | [177Lu]Lu-DOTA-TATE and [131I]MIBG Phenotypic Imaging-Based Therapy in Metastatic/Inoperable Pheochromocytomas and Paragangliomas: Comparative Results in a Single Center
The aim of the study is to assess phenotypic imaging patterns and the response to treatment with [177Lu]Lu-DOTA-TATE and/or [131I]MIBG in paragangliomas (PGLs) and pheochromocytomas (PHEOs), globally and according to the primary location.This is a 17-patient retrospective observational study, with 9 cases treated with [177Lu]Lu-DOTA-TATE and 8 with [131I]MIBG (37 total treatments). Functional imaging scans and treatment responses were studied in order to choose the best therapeutic option and to define the progression-free survival (PFS) and disease control rate (DCR) according to treatment modality and primary location.All patients were studied with phenotypic nuclear medicine images. Twelve of 17 patients were tested with both [123I]MIBG and somatostatin receptor images, and 6/12 showed appropriate expression of both targets to treatment in the phenotypic images. The rest of the patients were tested with one of the image modalities or only showed suitable uptake of a single radiotracer and were treated with the corresponding therapeutic option. [177Lu]Lu-DOTA-TATE PFS was 29 months with a DCR of 88.8%. [131I]MIBG PFS was 18.5 months with a 62.5% DCR. According to the primary location, the best PFS was in PHEOs treated with [177Lu]Lu-DOTA-TATE. Although the series are small due to the low disease prevalence and do not allow to yield statistically significant differences, this first study comparing [177Lu]Lu-DOTA-TATE and [131I]MIBG displays a trend to an overall longer PFS with [177Lu]Lu-DOTA-TATE, especially in the adrenal primary location. When both radionuclide targets are expressed, the patients' comorbidity and treatment effectiveness should be valued together with the intensity uptake in the phenotypic image in order to choose the best therapeutic option. These preliminary retrospective results reinforce the need for a prospective, multicentric trial to be confirmed.
2021-05-04 | GIPC2 is an endocrine-specific tumor suppressor gene for both sporadic and hereditary tumors of RET- and SDHB-, but not VHL-associated clusters of pheochromocytoma/paraganglioma
Abstract Pheochromocytoma/paraganglioma (PPGL) is an endocrine tumor of the chromaffin cells in the adrenal medulla or the paraganglia. Currently, about 70% of PPGLs can be explained by germline or somatic mutations in several broadly expressed susceptibility genes including RET , VHL, and SDHB , while for the remaining, mainly sporadic cases, the pathogenesis is still unclear. Even for known susceptible genes, how mutations in these mostly ubiquitous genes result in tissue-specific pathogenesis remains unanswered, and why RET -mutated tumors almost always occur in the adrenal while SDHB -mutated tumors mostly occur extra-adrenal remains a mystery. By analyzing 22 sporadic PPGLs using SNP 6.0 genotyping arrays combined with expression profiling of 4 normal and 4 tumor tissues, we identified GIPC2 , a gene located at 1p31.1 with preferential expression in adrenal and inducible by adrenal glucocorticoid, as a novel putative tumor suppressor gene for PPGLs. Copy number deletion and GIPC2 promoter hypermethylation but not GIPC2 mutation, accompanied with reduced GIPC2 expression, were observed in 39 of 55 PPGLs in our cohort. Examination of a published expression database consisting of 188 PPGLs found little GIPC2 expression in Cluster 1A (SDHx-associated) and Cluster 2A (NF1/RET-associated) tumors, but less pronounced reduction of GIPC2 expression in Cluster 1B (VHL-associated) and Cluster 2B/2C tumors. GIPC2 induced p27 , suppressed MAPK/ERK and HIF-1ɑ pathways as well as cancer cell proliferation. Overexpressing GIPC2 in PC12 cells inhibited tumor growth in nude mice. We found GIPC2 interacted with the nucleoprotein NONO and both proteins regulated p27 transcription through the same GGCC box on p27 promoter. Significantly, low expression of both GIPC2 and p27 was associated with shorter disease-free survival time of PPGLs patients in the TCGA database. We found that PPGL-causing mutations in RET and in SDHB could lead to primary rat adrenal chromaffin cell proliferation, ERK activation, and p27 downregulation, all requiring downregulating GIPC2. Notably, the RET-mutant effect required the presence of dexamethasone while the SDHB-mutant effect required its absence, providing a plausible explanation for the tumor location preference. In contrast, the PPGL-predisposing VHL mutations had no effect on proliferation and GIPC2 expression but caused p53 downregulation and reduced apoptosis in chromaffin cells compared with wild-type VHL. Thus, our study raises the importance of cortical hormone in PPGL development, and GIPC2 as a novel tumor suppressor provides a unified molecular mechanism for the tumorigenesis of both sporadic and hereditary tumors of Clusters 1A and 2A concerning SDHB and RET, but not tumors of Cluster 1B concerning VHL and other clusters.
2020-04-17 | Innovative approach to a functional mediastinal paraganglioma with anomalous coronary supply: a case report
Mediastinal paragangliomas (PGs) are rare and particularly challenging neuroendocrine tumours. Clinical presentation is heterogeneous and tumour resection can be challenging due to bleeding and the risk of catecholamine surges in functional tumours.A 36-year-old man with multiple cardiovascular risk factors was admitted with subacute heart failure. Investigations revealed a large non-metastatic functional mediastinal PG irrigated mainly by a left circumflex coronary anomalous feeder branch. The surgical risk was deemed very high due to patient comorbidities, tumour vascularization, and close relation to major thoracic structures. A multidisciplinary team decided to perform embolization of the anomalous coronary branch followed by peptide-receptor radionuclide therapy with 177-LuDOTATE aiming to decrease tumour size and perioperative risk. Follow-up studies showed a reduction in tumour vascularization, size, and hormonal production.The innovative strategy of combining embolization of the anomalous feeder branch with radionuclide therapy proved to be a promising approach.
antibodies
2023-03-24 | Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma.
The mechanisms triggering metastasis in pheochromocytoma/paraganglioma are unknown, hindering therapeutic options for patients with metastatic tumors (mPPGL). Herein we show by genomic profiling of a large cohort of mPPGLs that high mutational load, microsatellite instability and somatic copy-number alteration burden are associated with ATRX/TERT alterations and are suitable prognostic markers. Transcriptomic analysis defines the signaling networks involved in the acquisition of metastatic competence and establishes a gene signature related to mPPGLs, highlighting CDK1 as an additional mPPGL marker. Immunogenomics accompanied by immunohistochemistry identifies a heterogeneous ecosystem at the tumor microenvironment level, linked to the genomic subtype and tumor behavior. Specifically, we define a general immunosuppressive microenvironment in mPPGLs, the exception being PD-L1 expressing MAML3-related tumors. Our study reveals canonical markers for risk of metastasis, and suggests the usefulness of including immune parameters in clinical management for PPGL prognostication and identification of patients who might benefit from immunotherapy.
2019-04-01 | PD-L1 expression and association with malignant behavior in pheochromocytomas/paragangliomas
The immunosuppressive effect of the programmed death (PD)–1/PD-L1 pathway plays an important role in the treatment of a variety of tumors, such as lung and breast cancer, but there is little literature about PD-1/PD-L1 in pheochromocytomas/paragangliomas (PCCs/PGLs). We explored the relationship of PD-L1 and malignant behavior in 77 cases of PCC/PGL using immunohistochemistry (IHC) to assess protein expression and RNAscope to detect mRNA expression in 20 cases. The IHC data showed that 59.74% of the PCCs/PGLs expressed PD-L1, and the extent of expression was highly correlated with Ki-67 (P = .019) and hypertension (P = .013) but not with age, sex, tumor size, capsular invasion, tumor necrosis, relapse/distant metastasis, secretion of noradrenaline/adrenaline/dopamine, or diabetes mellitus. In addition, we found an excellent correlation of PD-L1 mRNA and protein expression with a κ coefficient of 0.828, and further stratification of the IHC and RNAscope findings showed high consistency (Pearson coefficient 0.753). The correlation of PD-L1 and Ki-67 indicated that PD-L1 could be considered a malignant proliferation biomarker for PCCs/PGLs, which would be a putative biomarker for anti–PD-L1 therapies.
2015-06-04 | 15 YEARS OF PARAGANGLIOMA: Imaging and imaging-based treatment of pheochromocytoma and paraganglioma
Although anatomic imaging to assess the precise localization of pheochromocytomas/paragangliomas (PHEOs/PGLs) is unavoidable before any surgical intervention on these tumors, functional imaging is becoming an inseparable portion of the imaging algorithm for these tumors. This review article presents applications of the most up-to-date functional imaging modalities and image-based treatment to PHEOs/PGLs patients. Functional imaging techniques provide whole-body localization (number of tumors present along with metastatic deposits) together with genetic-specific imaging approaches to PHEOs/PGLs, thus enabling highly specific and sensitive PHEO/PGL detection and delineation that now greatly impact the management of patients. Radionuclide imaging techniques also play a crucial role in the prediction of possible radioactive treatment options for PHEO/PGL. In contrast to previous imaging algorithms used for either assessement of these patients or their follow-up, endocrinologists, surgeons, oncologists, pediatricians, and other specialists require functional imaging before any therapeutic plan is outlined to the patient, and follow-up, especially in patients with metastatic disease, is based on the periodic use of functional imaging, often reducing or substituting for anatomical imaging. In similar specific indications, this will be further powered by using PET/MR in the assessment of these tumors. In the near future, it is expected that PHEO/PGL patients will benefit even more from an assessement of the functional characteristics of these tumors and new imaging-based treatment options. Finally, due to the use of new targeting moieties, gene-targeted radiotherapeutics and nanobodies-based theranostic approaches are expected to become a reality in the near future.
2014-04-16 | Usefulness of Succinate dehydrogenase B (SDHB) immunohistochemistry in guiding mutational screening among patients with pheochromocytoma-paraganglioma syndromes.
Genetic testing of pheochromocytomas ( PCC ) and paragangliomas ( PGL ), although expensive, is gradually becoming a part of the routine laboratory investigation for patients with PCC ‐ PGL syndrome. Recently, S uccinate dehydrogenase B ( SDHB ) immunochemistry has been shown to be an excellent indicator of germline mutations in the SDH genes and could help significantly reduce cost. This study assesses the utility of SDHB immunohistochemical analysis when used to guide genetic analysis, with emphasis on cost benefits it could provide in a resource‐limited setting. Forty‐four cases of PCC / PGL characterized by genetic analysis were included to determine their SDHB expression pattern by immunohistochemistry. SDHB antibody expression was negative among three cases each, with SDHB and SDHD mutations. Immunohistochemistry results were positive for all three cases of RET , a single case of neurofibromatosis and for two cases with V on H ippel‐ L indau ( VHL ) mutations while the remaining two cases with VHL mutations showed a diffuse ‘cytoplasmic blush’. Thirty of the remaining 31 samples demonstrated positive staining and were negative for mutations, while a lone sample that was negative for staining and mutation was not included in the final analysis as the internal control for the sample was not adequately stained. Cost analysis in our settings showed that triaging with SDHB immunohistochemistry could potentially reduce costs by USD 320–500 per patient. SDHB immunohistochemistry, when used as a guide to genetic testing, can significantly reduce the effort, time and costs of testing among patients with PCC ‐ PGL , a huge benefit in resource limited settings.
2011-07-14 | SDHA Immunohistochemistry Detects Germline SDHA Gene Mutations in Apparently Sporadic Paragangliomas and Pheochromocytomas
Abstract Context: Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA. A recent report described a patient with an abdominal paraganglioma, immunohistochemically negative for SDHA, and identified a causal germline mutation in SDHA. Objective: In this study, we evaluated the significance of SDHA immunohistochemistry in the identification of new patients with SDHA mutations. Setting: This study was performed in the Erasmus Medical Center in Rotterdam (The Netherlands) and the Université Paris Descartes in Paris (France). Methods: We investigated 316 pheochromocytomas and paragangliomas for SDHA expression. Sequence analysis of SDHA was performed on all tumors that were immunohistochemically negative for SDHA and on a subset of tumors immunohistochemically positive for SDHA. Results: Six tumors were immunohistochemically negative for SDHA. Four tumors from Dutch patients showed a germline c.91C→T SDHA gene mutation (p.Arg31X). Another tumor (from France) carried a germline SDHA missense mutation c.1753C→T (p.Arg585Trp). Loss of the wild-type SDHA allele was confirmed by loss of heterozygosity analysis. Sequence analysis of 35 SDHA immunohistochemically positive tumors did not reveal additional SDHA mutations. Conclusions: Our results demonstrate that SDHA immunohistochemistry on paraffin-embedded tumors can reveal the presence of SDHA germline mutations and allowed the identification of SDHA-related tumors in at least 3% of patients affected by apparently sporadic (para)sympathetic paragangliomas and pheochromocytomas.
small molecules
2026-07-30 | Fluctuating hypertension possibly leading to severe cardiomyopathy in SDHB-associated hereditary paraganglioma: from heart transplant candidacy to long-term lanreotide management: a case report
Introduction: Paragangliomas are rare catecholamine-secreting neuroendocrine tumors that can cause significant cardiovascular complications, including catecholamine-induced cardiomyopathy. While surgical resection is the standard of care, some patients are not candidates for surgery or heart transplantation due to tumor biology, genetic risk, or patient preference. Case summary: A 68-year-old man with longstanding hypertension, hereditary paraganglioma-pheochromocytoma syndrome (SDHB mutation), and advanced nonischemic cardiomyopathy was evaluated for heart transplantation. Imaging revealed a highly vascular retroperitoneal paraganglioma, and biochemical testing demonstrated markedly elevated chromogranin A with mildly increased plasma free normetanephrine. Biopsy confirmed paraganglioma. Due to transplant ineligibility related to malignancy risk and the patient's decision to decline surgical resection, medical therapy with lanreotide was initiated. Following treatment, the patient demonstrated biochemical improvement with declining chromogranin A levels, stabilization of blood pressure, improvement in B-type natriuretic peptide, modest recovery of left ventricular ejection fraction, and reduced metabolic activity on serial somatostatin receptor PET/CT imaging, with stable tumor size. Functional status remained excellent without further heart failure hospitalizations. Conclusion: This case highlights lanreotide as a potential non-surgical therapeutic option for paraganglioma-associated cardiomyopathy in select high-risk patients. Systemic tumor control may contribute to cardiovascular stabilization when surgical or transplant options are not feasible.
2026-07-28 | Clinical Impact of Germline Multigene Sequencing in Pediatric Cohorts with a Wide Spectrum of Neoplasms.
Cancer predisposition syndromes (CPSs) account for 8.5-18% of all childhood cancer cases. Most of them are inherited in an autosomal dominant pattern; consequently, there is a 50% risk of transmission to offspring. Early detection of CPSs is crucial for choosing patient treatment strategies and for counseling in the family. This study enrolled 886 pediatric patients with hematologic and solid neoplasms from prospective and retrospective cohorts (2018-2025). Clinical exome or multigene panel sequencing was used to analyze blood DNA. Overall, 186 pathogenic/likely pathogenic (PLP) variants in cancer-associated genes were identified in 176/886 (20%) of patients, and the most frequently mutated were the NF1 (n = 35) and TP53 (n = 18) genes. Among the 186 PLP variants, 126/886 (14.2%) were causative for pediatric neoplasms, while 56/886 (6.3%) were heterozygous mutations associated with adult-onset CPSs affecting DNA repair. The highest total mutation rate was revealed in retinoblastoma (80%), peripheral nerve sheath tumors (60%), and pheochromocytoma/paraganglioma (47%), while the lowest rate was found in hematologic malignancies (4.6%) and neuroblastoma (12%). The wide range and high frequency of deleterious variants in pediatric patients, especially in those with solid tumors, highlights the importance of multigene panel sequencing for the accurate determination of CPSs.
2026-07-22 | A multistakeholder call for belzutifan biomarker data in advanced pheochromocytoma and paraganglioma.
The HIF-2α inhibitor belzutifan was recently U.S. Food and Drug Administration (FDA)-approved for advanced pheochromocytoma/paraganglioma. This multistakeholder article calls for clinical-trial genomic correlates and outcome data to clarify efficacy across these molecularly heterogeneous neuroendocrine tumors.
2026-02-19 | Succinate dehydrogenase-deficient cancer cells have increased susceptibility to Ym155-induced DNA damage
The hereditary pheochromocytoma and paraganglioma (hPPGL) syndrome, caused by germline mutations in succinate dehydrogenase (SDHx) genes, predisposes individuals to pheochromocytomas (Pheo), paragangliomas (PGLs), renal cell carcinoma (RCC) and gastrointestinal stromal tumors (GISTs). Notably, tumors with succinate dehydrogenase subunit B (SDHB) deficiency demonstrate an increased metastatic risk and current systemic treatments remain only palliative. Hence, discovering novel therapeutic avenues to improve SDHB cancer prognosis is an urgent need. Here, we leveraged human SDHB-deficient UOK269 RCC cells (SDHB-KO) and isogenic SDHB-reconstituted control cells (SDHB-WT) to discover SDH-dependent mitochondria-directed cytotoxic agents. Given the reduced ATP-generating capacity of SDHB-KO cells, we hypothesized that they would be uniquely sensitive to futile cycle induction with mitochondrial ionophores. Indeed, ionophores exhibited preferential cytotoxicity toward SDHB-KO cells. However, the mitochondria-directed chemotherapeutic compound Ym155 demonstrated more potent and dramatic preferential cytotoxicity toward SDHB-KO cells. Importantly, SDH-dependent cytotoxicity of Ym155 was validated in multiple cell models, including primary human pheochromocytoma cells, a mouse pheochromocytoma (MPC) cell line and primary SDHB-deficient mouse kidney cells. Notably, genetic evidence of Ym155 synthetic lethality with SDHB deficiency was buttressed in additional cell models using two chemical inhibitors of SDH enzyme activity. Mechanistically, SDH deficiency sensitized cells to Ym155-induced DNA damage. Strikingly, SDH-dependent Ym155 sensitivity was recapitulated by inhibition of the histone demethylase KDM4, a downstream consequence of SDH deficiency. In summary, accumulation of succinate in SDH-deficient tumors inhibited KDM4 activity, impaired DNA repair and yielded enhanced susceptibility to Ym155-induced reactive oxygen species (ROS) generation. The identified intrinsic susceptibilities of SDHB-deficient cancers have the potential to be therapeutically leveraged.
2026-02-03 | Targeting HIF-2α in renal cell carcinoma: Expanding upon belzutifan.
Clear cell renal cell carcinoma (ccRCC) is a common subtype of kidney cancer driven by the inactivation of the von Hippel-Lindau (VHL) gene, leading to the accumulation of hypoxia-inducible factor (HIF)-2α and tumorigenesis. Targeting HIF-2α has emerged as a promising therapeutic strategy culminating in the development of a first-in-class inhibitor, belzutifan, invented by Peloton Therapeutics and marketed by Merck. This article presents the journey to belzutifan and subsequent developments. We discuss the structure-based design leading to the first-in-human drug, PT2385, as well as subsequent modifications to improve pharmacokinetic properties leading to PT2977/belzutifan. Detailed analyses are presented of key HIF-2α structural features, the mechanism of drug action, and how this family of drugs performed in preclinical models. Belzutifan's impact on patients with VHL syndrome, sporadic advanced ccRCC and pheochromocytoma/paraganglioma is discussed, three areas where belzutifan has obtained Food and Drug Administration approval. Drug combination strategies, mechanisms of resistance, and emerging strategies to overcome them, including siRNA-based therapeutics, are presented. Alternative HIF-2α inhibitors are examined, including NKT2152 and AB521. By expanding upon the foundation established by belzutifan, the field is poised for further therapeutic advances.
gene therapies
2025-12-24 | Precision Care for Hereditary Urologic Cancers: Genetic Testing, Counseling, Surveillance, and Therapeutic Implications.
Hereditary predisposition substantially shapes prevention and management across urologic oncology. This narrative review synthesizes contemporary, practice-oriented guidance on whom to test, what to test, how to act on results, and how to implement care equitably for hereditary forms of prostate cancer, renal cell carcinoma (RCC), urothelial carcinoma, pheochromocytoma/paraganglioma (PPGL), and adrenocortical carcinoma (ACC). We delineate between forms of indication-driven germline testing (e.g., universal testing in metastatic prostate cancer; early-onset, bilateral/multifocal, or syndromic RCC; reflex tumor mismatch repair (MMR)/microsatellite instability (MSI) screening in upper-tract urothelial carcinoma (UTUC); universal testing in PPGL; universal TP53 testing in ACC) and pair these strategies with minimum actionable gene sets and syndrome-specific surveillance frameworks. Key points include targeted prostate-specific antigen screening in BRCA2 carriers and the impact of BRCA/ATM variants on reclassification during active surveillance; major hereditary RCC syndromes with genotype-tailored surveillance and pathway-directed therapy (e.g., HIF-2α inhibition for von Hippel-Lindau disease); UTUC/bladder cancer in Lynch syndrome with tumor MMR/MSI screening, annual urinalysis (selective cytology), and immunotherapy opportunities in deficient MMR disease/MSI-H; PPGL management emphasizing universal germline testing, intensified surveillance for SDHB, cortical-sparing adrenalectomy, and emerging HIF-2α inhibition; and ACC care modified by Li-Fraumeni syndrome (minimization of radiation/genotoxic therapy with whole-body imaging surveillance). Testicular germ cell tumor remains largely polygenic, with no routine germline testing in typical presentations. Finally, we provide pre-/post-test genetic-counseling checklists and mainstreamed workflows with equity metrics to operationalize precision care and close real-world access gaps.
2019-05-23 | 65 YEARS OF THE DOUBLE HELIX: Genetics informs precision practice in the diagnosis and management of pheochromocytoma.
Although the authors of the present review have contributed to genetic discoveries in the field of pheochromocytoma research, we can legitimately ask whether these advances have led to improvements in the diagnosis and management of patients with pheochromocytoma. The answer to this question is an emphatic Yes! In the field of molecular genetics, the well-established axiom that familial (genetic) pheochromocytoma represents 10% of all cases has been overturned, with >35% of cases now attributable to germline disease-causing mutations. Furthermore, genetic pheochromocytoma can now be grouped into five different clinical presentation types in the context of the ten known susceptibility genes for pheochromocytoma-associated syndromes. We now have the tools to diagnose patients with genetic pheochromocytoma, identify germline mutation carriers and to offer gene-informed medical management including enhanced surveillance and prevention. Clinically, we now treat an entire family of tumors of the paraganglia, with the exact phenotype varying by specific gene. In terms of detection and classification, simultaneous advances in biochemical detection and imaging localization have taken place, and the histopathology of the paraganglioma tumor family has been revised by immunohistochemical-genetic classification by gene-specific antibody immunohistochemistry. Treatment options have also been substantially enriched by the application of minimally invasive and adrenal-sparing surgery. Finally and most importantly, it is now widely recognized that patients with genetic pheochromocytoma/paraganglioma syndromes should be treated in specialized centers dedicated to the diagnosis, treatment and surveillance of this rare neoplasm.
2018-08-19 | Whole Exome Sequencing Uncovers Germline Variants of Cancer-Related Genes in Sporadic Pheochromocytoma
Pheochromocytomas (PCCs) show the highest degree of heritability in human neoplasms. However, despite the wide number of alterations until now reported in PCCs, it is likely that other susceptibility genes remain still unknown, especially for those PCCs not clearly syndromic.Whole exome sequencing of tumor DNA was performed on a set of twelve PCCs clinically defined as sporadic.About 50% of PCCs examined had somatic mutations on the known susceptibility VHL, NF1, and RET genes. In addition to these driver events, mutations on SYNE1, ABCC10, and RAD54B genes were also detected. Moreover, extremely rare germline variants were present in half of the sporadic PCC samples analyzed, in particular variants of MAX and SAMD9L were detected in the germline of cases wild-type for mutations in the known susceptibility genes.Additional somatic passenger mutations can be associated with known susceptibility VHL, NF1, and RET genes in PCCs, and a wide number of germline variants with still unknown clinical significance can be detected in these patients. Therefore, many efforts should be aimed to better define the pathogenetic role of all these germline variants for discovering novel potential therapeutic targets for this disease still orphan of effective treatments.
2014-03-27 | Opposing effects of HIF1α and HIF2α on chromaffin cell phenotypic features and tumor cell proliferation: Insights from MYC‐associated factor X
Pheochromocytomas and paragangliomas (PPGLs) are catecholamine‐producing chromaffin cell tumors with diverse phenotypic features reflecting mutations in numerous genes, including MYC‐associated factor X ( MAX ). To explore whether phenotypic differences among PPGLs reflect a MAX‐mediated mechanism and opposing influences of hypoxia‐inducible factor (HIF)s HIF2α and HIF1α, we combined observational investigations in PPGLs and gene‐manipulation studies in two pheochromocytoma cell lines. Among PPGLs from 140 patients, tumors due to MAX mutations were characterized by gene expression profiles and intermediate phenotypic features that distinguished these tumors from other PPGLs, all of which fell into two expression clusters: one cluster with low expression of HIF2α and mature phenotypic features and the other with high expression of HIF2α and immature phenotypic features due to mutations stabilizing HIFs. Max ‐mutated tumors distributed to a distinct subcluster of the former group. In cell lines lacking Max , re‐expression of the gene resulted in maturation of phenotypic features and decreased cell cycle progression. In cell lines lacking Hif2α , overexpression of the gene led to immature phenotypic features, failure of dexamethasone to induce differentiation and increased proliferation. HIF1α had opposing actions to HIF2α in both cell lines, supporting evolving evidence of their differential actions on tumorigenic processes via a MYC/MAX‐related pathway. Requirement of a fully functional MYC/MAX complex to facilitate differentiation explains the intermediate phenotypic features in tumors due to MAX mutations. Overexpression of HIF2α in chromaffin cell tumors due to mutations affecting HIF stabilization explains their proliferative features and why the tumors fail to differentiate even when exposed locally to adrenal steroids.
2011-12-01 | Is genetic screening indicated in apparently sporadic pheochromocytomas and paragangliomas?
Pheochromocytoma (Pheo) is usually considered a sporadic disease. Recently, an increasing rate of genetically based tumors has been reported. However, the need for systematic screening of unsuspected germline mutations in apparently sporadic forms is still debated. This study aimed to assess the effective rate of germline mutations causing Pheo and Paraganglioma (PGL), and the role of systematic genetic screening.Demographics, clinical, and genetic evaluation were performed in a series of 71 patients with Pheo and/or PGL.Twelve patients had evident inherited/familial disease at presentation: NF1 (n = 4); MEN2 (n = 4), and familial Pheo/PGL (n = 4). Among 59 patients with apparently sporadic disease, unsuspected germline mutations occurred in 8 cases: TMEM127 (n = 4), SDHB (n = 2), VHL (n = 1), SDHC (n = 1). No differences were found between hereditary and sporadic disease concerning age, sex, and tumor size; bilateral Pheo and/or PGL and recurrences occurred most often in hereditary disease.Hereditary Pheo and/or PGL are frequent (28.2%). Inheritance is evident at presentation only in 16.9% of cases; 13.6% of apparently sporadic variants are genetically determined. Despite increased costs, systematic genetic screening might be useful because it might lead to a stricter follow-up, early diagnosis of recurrences in index cases and presymptomatic detection of disease in relatives.
proteins
2024-04-15 | PD23-02 IMPACT OF TRAP1 ON COMPLEX II ASSEMBLY IN CELLS WITH PATHOGENIC FAMILIAL PHEOCHROMOCYTOMA ASSOCIATED MUTATIONS
You have accessJournal of UrologyAdrenal (PD23)1 May 2024PD23-02 IMPACT OF TRAP1 ON COMPLEX II ASSEMBLY IN CELLS WITH PATHOGENIC FAMILIAL PHEOCHROMOCYTOMA ASSOCIATED MUTATIONS Nathan Nahhas and Mark R. Woodford Nathan NahhasNathan Nahhas and Mark R. WoodfordMark R. Woodford View All Author Informationhttps://doi.org/10.1097/01.JU.0001008664.51020.58.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The succinate dehydrogenase enzyme (SDH) is integral to the oxidative phosphorylation pathway, and has been found to play a role in tumor oncogenesis and metabolism. SDH loss of function mutations are associated with pheochromocytomas and paragangliomas. Germline mutations have also been associated with familial tumor syndromes. No targeted pharmaceutical therapies are available for these tumors. The mitochondrial chaperone TNF-receptor associated protein 1 (TRAP1) and SDHAF2 assembly factor have been shown to participate in SDH complex assembly, but their functional pathway is not fully elucidated. TRAP1 expression is upregulated in multiple cancer models, and previous work has shown that inhibition of TRAP1 induces apoptosis in tumor cells. The objective of our work was to determine the mechanism of uncharacterized pathogenic SDH and SDHAF2 mutations and what role TRAP1 plays in this process. METHODS: DNA plasmid transfection of mutants clinically associated with pheochromocytoma in 293 wild type and SDHB subunit knock out cells was used to modulate levels of SDHB and SDHAF2 proteins. Immunoblotting and immunoprecipitation were used with submitochondrial fractionation to evaluate protein expression and interaction in the setting of TRAP1 drug inhibition. In vitro enzymatic assays and real-time respiratory assays were used to evaluate SDH activity. RESULTS: SDHB mutation resulted in impaired binding to the SDHA subunit and failed to rescue respiratory function compared to wild type. The pathogenic SDHAF2-G78R mutant also exhibited reduced binding to SDHA and decreased SDH activity in vitro. Interestingly, we were not able to observe interaction between TRAP1 and SDHAF2. Further, TRAP1 knockout compromised binding between SDHAF2 and SDHA. This indicated that TRAP1 is unable to incorporate pathogenic mutant proteins into functional SDH complexes. CONCLUSIONS: TRAP1 has a regulatory role in assembly of functional SDH complexes, and TRAP1 binding has been shown to inhibit the function of SDH. However, TRAP1 fails to bind with pathogenic mutations of SDHB, leading to a lack of respiratory function. In both TRAP1 knockout and pathogenic SDHAF2 mutations, SDH complexes fail to assemble, suggesting that TRAP1 and SDHAF2 are both required for SDH complex function. Our data suggests TRAP1 and SDHAF2 act in a mutually exclusive manner for SDH complex assembly. As TRAP1 regulates respiratory function, TRAP1 modification therapy could be explored for patients with familial pheochromocytoma syndrome or tumors with metabolic SDH dysregulation. Source of Funding: Upstate Medical University Department of Urology,Upstate Medical University Department of Biochemistry & Molecular Biology, Upstate Cancer Center at SUNY Upstate Medical University © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e523 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Nathan Nahhas More articles by this author Mark R. Woodford More articles by this author Expand All Advertisement PDF downloadLoading ...
2023-07-01 | Unusual case report of malignant pheochromocytoma presenting with STEMI
Pheochromocytomas (PHEOs) are a group of tumours that leads to multiple symptoms and can induce hypercoagulability and promote thrombosis. Pheochromocytomas may also present without elevated serum and urinary markers. We aimed to provide tips and tricks for the diagnostic and therapeutic management of an unusual case of PHEOs.Thirty-four-year-old woman with the unremarkable medical history presented with epigastric pain and dyspnoea. Electrocardiogram showed ST-segment elevation in the inferior limb leads. She underwent an emergency coronary angiogram, which showed a high thrombus burden in the distal right coronary artery. A subsequent echocardiogram demonstrated a 31 × 33 mm right atrial mass adhering to the inferior vena cava and abdominal computed tomography (CT) scan revealed a 113 × 85 mm necrotic mass in the left adrenal bed, with tumour thrombus extending proximally to the confluence of hepatic veins immediately inferior to the right atrium and distally to iliac vein bifurcation. Blood parameters, thrombophilia panel, vanillylmandelic acid, 5 hydroxy indole acetic acid, and homovanillic acid levels were normal. Tissue sampling confirmed the diagnosis of PHEOs. The surgical procedure was not planned due to the presence of metastatic foci on imaging, including positron emission tomography (PET)-CT. Anticoagulation with rivaroxaban and treatment with 177Lu-DOTATATE-based peptide receptor radionuclide therapy (PRRT) was initiated.The coexistence of arterial and venous thrombosis is extremely rare in patients with PHEOs. Multidisciplinary approaches are required for the care of such patients. Catecholamines likely contributed to the development of thrombosis in our patient. Early recognition of PHEOs is the key point to ameliorate clinical outcomes.
2022-02-07 | [177Lu]Lu-DOTA-TATE and [131I]MIBG Phenotypic Imaging-Based Therapy in Metastatic/Inoperable Pheochromocytomas and Paragangliomas: Comparative Results in a Single Center
The aim of the study is to assess phenotypic imaging patterns and the response to treatment with [177Lu]Lu-DOTA-TATE and/or [131I]MIBG in paragangliomas (PGLs) and pheochromocytomas (PHEOs), globally and according to the primary location.This is a 17-patient retrospective observational study, with 9 cases treated with [177Lu]Lu-DOTA-TATE and 8 with [131I]MIBG (37 total treatments). Functional imaging scans and treatment responses were studied in order to choose the best therapeutic option and to define the progression-free survival (PFS) and disease control rate (DCR) according to treatment modality and primary location.All patients were studied with phenotypic nuclear medicine images. Twelve of 17 patients were tested with both [123I]MIBG and somatostatin receptor images, and 6/12 showed appropriate expression of both targets to treatment in the phenotypic images. The rest of the patients were tested with one of the image modalities or only showed suitable uptake of a single radiotracer and were treated with the corresponding therapeutic option. [177Lu]Lu-DOTA-TATE PFS was 29 months with a DCR of 88.8%. [131I]MIBG PFS was 18.5 months with a 62.5% DCR. According to the primary location, the best PFS was in PHEOs treated with [177Lu]Lu-DOTA-TATE. Although the series are small due to the low disease prevalence and do not allow to yield statistically significant differences, this first study comparing [177Lu]Lu-DOTA-TATE and [131I]MIBG displays a trend to an overall longer PFS with [177Lu]Lu-DOTA-TATE, especially in the adrenal primary location. When both radionuclide targets are expressed, the patients' comorbidity and treatment effectiveness should be valued together with the intensity uptake in the phenotypic image in order to choose the best therapeutic option. These preliminary retrospective results reinforce the need for a prospective, multicentric trial to be confirmed.
2021-05-04 | GIPC2 is an endocrine-specific tumor suppressor gene for both sporadic and hereditary tumors of RET- and SDHB-, but not VHL-associated clusters of pheochromocytoma/paraganglioma
Abstract Pheochromocytoma/paraganglioma (PPGL) is an endocrine tumor of the chromaffin cells in the adrenal medulla or the paraganglia. Currently, about 70% of PPGLs can be explained by germline or somatic mutations in several broadly expressed susceptibility genes including RET , VHL, and SDHB , while for the remaining, mainly sporadic cases, the pathogenesis is still unclear. Even for known susceptible genes, how mutations in these mostly ubiquitous genes result in tissue-specific pathogenesis remains unanswered, and why RET -mutated tumors almost always occur in the adrenal while SDHB -mutated tumors mostly occur extra-adrenal remains a mystery. By analyzing 22 sporadic PPGLs using SNP 6.0 genotyping arrays combined with expression profiling of 4 normal and 4 tumor tissues, we identified GIPC2 , a gene located at 1p31.1 with preferential expression in adrenal and inducible by adrenal glucocorticoid, as a novel putative tumor suppressor gene for PPGLs. Copy number deletion and GIPC2 promoter hypermethylation but not GIPC2 mutation, accompanied with reduced GIPC2 expression, were observed in 39 of 55 PPGLs in our cohort. Examination of a published expression database consisting of 188 PPGLs found little GIPC2 expression in Cluster 1A (SDHx-associated) and Cluster 2A (NF1/RET-associated) tumors, but less pronounced reduction of GIPC2 expression in Cluster 1B (VHL-associated) and Cluster 2B/2C tumors. GIPC2 induced p27 , suppressed MAPK/ERK and HIF-1ɑ pathways as well as cancer cell proliferation. Overexpressing GIPC2 in PC12 cells inhibited tumor growth in nude mice. We found GIPC2 interacted with the nucleoprotein NONO and both proteins regulated p27 transcription through the same GGCC box on p27 promoter. Significantly, low expression of both GIPC2 and p27 was associated with shorter disease-free survival time of PPGLs patients in the TCGA database. We found that PPGL-causing mutations in RET and in SDHB could lead to primary rat adrenal chromaffin cell proliferation, ERK activation, and p27 downregulation, all requiring downregulating GIPC2. Notably, the RET-mutant effect required the presence of dexamethasone while the SDHB-mutant effect required its absence, providing a plausible explanation for the tumor location preference. In contrast, the PPGL-predisposing VHL mutations had no effect on proliferation and GIPC2 expression but caused p53 downregulation and reduced apoptosis in chromaffin cells compared with wild-type VHL. Thus, our study raises the importance of cortical hormone in PPGL development, and GIPC2 as a novel tumor suppressor provides a unified molecular mechanism for the tumorigenesis of both sporadic and hereditary tumors of Clusters 1A and 2A concerning SDHB and RET, but not tumors of Cluster 1B concerning VHL and other clusters.
2020-04-17 | Innovative approach to a functional mediastinal paraganglioma with anomalous coronary supply: a case report
Mediastinal paragangliomas (PGs) are rare and particularly challenging neuroendocrine tumours. Clinical presentation is heterogeneous and tumour resection can be challenging due to bleeding and the risk of catecholamine surges in functional tumours.A 36-year-old man with multiple cardiovascular risk factors was admitted with subacute heart failure. Investigations revealed a large non-metastatic functional mediastinal PG irrigated mainly by a left circumflex coronary anomalous feeder branch. The surgical risk was deemed very high due to patient comorbidities, tumour vascularization, and close relation to major thoracic structures. A multidisciplinary team decided to perform embolization of the anomalous coronary branch followed by peptide-receptor radionuclide therapy with 177-LuDOTATE aiming to decrease tumour size and perioperative risk. Follow-up studies showed a reduction in tumour vascularization, size, and hormonal production.The innovative strategy of combining embolization of the anomalous feeder branch with radionuclide therapy proved to be a promising approach.
antibodies
2023-03-24 | Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma.
The mechanisms triggering metastasis in pheochromocytoma/paraganglioma are unknown, hindering therapeutic options for patients with metastatic tumors (mPPGL). Herein we show by genomic profiling of a large cohort of mPPGLs that high mutational load, microsatellite instability and somatic copy-number alteration burden are associated with ATRX/TERT alterations and are suitable prognostic markers. Transcriptomic analysis defines the signaling networks involved in the acquisition of metastatic competence and establishes a gene signature related to mPPGLs, highlighting CDK1 as an additional mPPGL marker. Immunogenomics accompanied by immunohistochemistry identifies a heterogeneous ecosystem at the tumor microenvironment level, linked to the genomic subtype and tumor behavior. Specifically, we define a general immunosuppressive microenvironment in mPPGLs, the exception being PD-L1 expressing MAML3-related tumors. Our study reveals canonical markers for risk of metastasis, and suggests the usefulness of including immune parameters in clinical management for PPGL prognostication and identification of patients who might benefit from immunotherapy.
2019-04-01 | PD-L1 expression and association with malignant behavior in pheochromocytomas/paragangliomas
The immunosuppressive effect of the programmed death (PD)–1/PD-L1 pathway plays an important role in the treatment of a variety of tumors, such as lung and breast cancer, but there is little literature about PD-1/PD-L1 in pheochromocytomas/paragangliomas (PCCs/PGLs). We explored the relationship of PD-L1 and malignant behavior in 77 cases of PCC/PGL using immunohistochemistry (IHC) to assess protein expression and RNAscope to detect mRNA expression in 20 cases. The IHC data showed that 59.74% of the PCCs/PGLs expressed PD-L1, and the extent of expression was highly correlated with Ki-67 (P = .019) and hypertension (P = .013) but not with age, sex, tumor size, capsular invasion, tumor necrosis, relapse/distant metastasis, secretion of noradrenaline/adrenaline/dopamine, or diabetes mellitus. In addition, we found an excellent correlation of PD-L1 mRNA and protein expression with a κ coefficient of 0.828, and further stratification of the IHC and RNAscope findings showed high consistency (Pearson coefficient 0.753). The correlation of PD-L1 and Ki-67 indicated that PD-L1 could be considered a malignant proliferation biomarker for PCCs/PGLs, which would be a putative biomarker for anti–PD-L1 therapies.
2015-06-04 | 15 YEARS OF PARAGANGLIOMA: Imaging and imaging-based treatment of pheochromocytoma and paraganglioma
Although anatomic imaging to assess the precise localization of pheochromocytomas/paragangliomas (PHEOs/PGLs) is unavoidable before any surgical intervention on these tumors, functional imaging is becoming an inseparable portion of the imaging algorithm for these tumors. This review article presents applications of the most up-to-date functional imaging modalities and image-based treatment to PHEOs/PGLs patients. Functional imaging techniques provide whole-body localization (number of tumors present along with metastatic deposits) together with genetic-specific imaging approaches to PHEOs/PGLs, thus enabling highly specific and sensitive PHEO/PGL detection and delineation that now greatly impact the management of patients. Radionuclide imaging techniques also play a crucial role in the prediction of possible radioactive treatment options for PHEO/PGL. In contrast to previous imaging algorithms used for either assessement of these patients or their follow-up, endocrinologists, surgeons, oncologists, pediatricians, and other specialists require functional imaging before any therapeutic plan is outlined to the patient, and follow-up, especially in patients with metastatic disease, is based on the periodic use of functional imaging, often reducing or substituting for anatomical imaging. In similar specific indications, this will be further powered by using PET/MR in the assessment of these tumors. In the near future, it is expected that PHEO/PGL patients will benefit even more from an assessement of the functional characteristics of these tumors and new imaging-based treatment options. Finally, due to the use of new targeting moieties, gene-targeted radiotherapeutics and nanobodies-based theranostic approaches are expected to become a reality in the near future.
2014-04-16 | Usefulness of Succinate dehydrogenase B (SDHB) immunohistochemistry in guiding mutational screening among patients with pheochromocytoma-paraganglioma syndromes.
Genetic testing of pheochromocytomas ( PCC ) and paragangliomas ( PGL ), although expensive, is gradually becoming a part of the routine laboratory investigation for patients with PCC ‐ PGL syndrome. Recently, S uccinate dehydrogenase B ( SDHB ) immunochemistry has been shown to be an excellent indicator of germline mutations in the SDH genes and could help significantly reduce cost. This study assesses the utility of SDHB immunohistochemical analysis when used to guide genetic analysis, with emphasis on cost benefits it could provide in a resource‐limited setting. Forty‐four cases of PCC / PGL characterized by genetic analysis were included to determine their SDHB expression pattern by immunohistochemistry. SDHB antibody expression was negative among three cases each, with SDHB and SDHD mutations. Immunohistochemistry results were positive for all three cases of RET , a single case of neurofibromatosis and for two cases with V on H ippel‐ L indau ( VHL ) mutations while the remaining two cases with VHL mutations showed a diffuse ‘cytoplasmic blush’. Thirty of the remaining 31 samples demonstrated positive staining and were negative for mutations, while a lone sample that was negative for staining and mutation was not included in the final analysis as the internal control for the sample was not adequately stained. Cost analysis in our settings showed that triaging with SDHB immunohistochemistry could potentially reduce costs by USD 320–500 per patient. SDHB immunohistochemistry, when used as a guide to genetic testing, can significantly reduce the effort, time and costs of testing among patients with PCC ‐ PGL , a huge benefit in resource limited settings.
2011-07-14 | SDHA Immunohistochemistry Detects Germline SDHA Gene Mutations in Apparently Sporadic Paragangliomas and Pheochromocytomas
Abstract Context: Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA. A recent report described a patient with an abdominal paraganglioma, immunohistochemically negative for SDHA, and identified a causal germline mutation in SDHA. Objective: In this study, we evaluated the significance of SDHA immunohistochemistry in the identification of new patients with SDHA mutations. Setting: This study was performed in the Erasmus Medical Center in Rotterdam (The Netherlands) and the Université Paris Descartes in Paris (France). Methods: We investigated 316 pheochromocytomas and paragangliomas for SDHA expression. Sequence analysis of SDHA was performed on all tumors that were immunohistochemically negative for SDHA and on a subset of tumors immunohistochemically positive for SDHA. Results: Six tumors were immunohistochemically negative for SDHA. Four tumors from Dutch patients showed a germline c.91C→T SDHA gene mutation (p.Arg31X). Another tumor (from France) carried a germline SDHA missense mutation c.1753C→T (p.Arg585Trp). Loss of the wild-type SDHA allele was confirmed by loss of heterozygosity analysis. Sequence analysis of 35 SDHA immunohistochemically positive tumors did not reveal additional SDHA mutations. Conclusions: Our results demonstrate that SDHA immunohistochemistry on paraffin-embedded tumors can reveal the presence of SDHA germline mutations and allowed the identification of SDHA-related tumors in at least 3% of patients affected by apparently sporadic (para)sympathetic paragangliomas and pheochromocytomas.
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Drug Discovery Landscape
1 orphan drug designation for Hereditary pheochromocytoma-paraganglioma, including 1 approved therapy.
1 orphan drug designation for Hereditary pheochromocytoma-paraganglioma, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Iobenguane I 123 [AdreView] | small molecules | FDA | Approved | GE Healthcare, Inc. |
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