RARE DISEASE
Sporadic pheochromocytoma/secreting paraganglioma
Sporadic pheochromocytoma/secreting paraganglioma
Sporadic pheochromocytoma/secreting paraganglioma
Drug discovery
2
drugs
With orphan designations
Overview
Sporadic pheochromocytomas and secreting paragangliomas are rare neuroendocrine tumors arising from adrenal medulla (pheochromocytomas) or extra-adrenal ganglia (paragangliomas). These tumors secrete catecholamines, leading to hypertension, headaches, palpitations, and cardiovascular complications. Diagnosis involves biochemical testing for metanephrines and imaging (CT/MRI). While most are benign, 15–25% become metastatic [1][6][12]. Genetic testing is recommended, as up to 40% of cases have hereditary links, though sporadic tumors typically present later [1][6][16].
Burden
Morbidity: Cardiovascular crises (e.g., stroke, cardiomyopathy) occur in 15–20% of patients pre-diagnosis [1][6].
Metastasis: 15–25% develop metastatic disease, with 5-year survival dropping to 40–60% [6][17].
Quality of life: Median 2-year diagnostic delay; 81% report moderate-severe financial distress and emotional toll due to specialized care needs [4][9].
Therapies
First-line: Surgical resection (laparoscopic for tumors <5 cm; open adrenalectomy for larger/metastatic tumors) with preoperative α-blockers (phenoxybenzamine/doxazosin) and β-blockers [3][12][18].
Metastatic disease: ¹³¹I-MIBG therapy, peptide receptor radionuclide therapy (¹⁷⁷Lu-DOTATATE), or chemotherapy (cyclophosphamide/vincristine/dacarbazine) [8][13][18].
Emerging options: Tyrosine kinase inhibitors (sunitinib, cabozantinib) and clinical trials evaluating HIF2α inhibitors or combination therapies (temozolomide/olaparib) [13][18].
Categories: rare endocrine diseases, rare neoplastic diseases
Research Papers
133 drug discovery papers about Sporadic pheochromocytoma/secreting paraganglioma, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
133 drug discovery papers about Sporadic pheochromocytoma/secreting paraganglioma, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2024-09-25 | Current views on the role of HIF-2α in the pathogenesis and syndromic presentation of pheochromocytoma and paraganglioma
Pathogenic variants (PVs) in EPAS1, which encodes hypoxia-inducible factor-2α (HIF-2α), could be the underlying genetic cause of about 3%-6% of pheochromocytoma and paragangliomas (PPGLs). EPAS1-related PPGLs may occur as isolated tumors or as part of Pacak-Zhuang Syndrome (PZS) with two or more of a triad of PPGL, polycythemia, and somatostatinoma. HIF-2α plays a critical role in the regulation of the cellular hypoxia pathway. When a gain-of-function PV is acquired, HIF-2α evades steady-state hydroxylation by the prolyl hydroxylase type 2 (PHD2), which accelerates von Hippel-Lindau (VHL)-mediated proteasomal degradation. In this situation, HIF-2α is stabilized and can translocate to the nucleus, inducing the expression of several genes involved in tumorigenesis. This leads to the development of PPGL and other manifestations of PZS. EPAS1-related PPGLs usually occur in the second or third decade of life, more frequently in females, and are usually multiple, adrenal and extra-adrenal, and norepinephrine-secreting. In addition, these tumors carry an increased metastatic potential and have been reported with metastatic disease in up to 30% of cases. While polycythemia is fairly common in PZS, somatostatinomas are rare. It has been suggested that the character of the acquired PV in EPAS1, which affects its binding to PHD2, correlates with certain phenotypes in PZS. PVs in EPAS1 that have been found in related sporadic PPGLs have also been associated with hypoxic conditions including cyanotic congenital heart disease, hemoglobinopathies and high altitude. Understanding the hypoxia pathway and its role in the pathogenesis of PPGL may open a new avenue for developing effective therapies for these tumors. Indeed, one of these therapies is Belzutifan, a HIF-2α inhibitor that is being tested in the treatment of metastatic PPGLs.
2023-10-05 | The connection between tricarboxylic acid cycle enzyme mutations and pseudohypoxic signaling in pheochromocytoma and paraganglioma
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells, holding significant clinical importance due to their capacity for excessive catecholamine secretion and associated cardiovascular complications. Roughly 80% of cases are associated with genetic mutations. Based on the functionality of these mutated genes, PPGLs can be categorized into distinct molecular clusters: the pseudohypoxia signaling cluster (Cluster-1), the kinase signaling cluster (Cluster-2), and the WNT signaling cluster (Cluster-3). A pivotal factor in the pathogenesis of PPGLs is hypoxia-inducible factor-2α (HIF2α), which becomes upregulated even under normoxic conditions, activating downstream transcriptional processes associated with pseudohypoxia. This adaptation provides tumor cells with a growth advantage and enhances their ability to thrive in adverse microenvironments. Moreover, pseudohypoxia disrupts immune cell communication, leading to the development of an immunosuppressive tumor microenvironment. Within Cluster-1a, metabolic perturbations are particularly pronounced. Mutations in enzymes associated with the tricarboxylic acid (TCA) cycle, such as succinate dehydrogenase (SDHx), fumarate hydratase (FH), isocitrate dehydrogenase (IDH), and malate dehydrogenase type 2 (MDH2), result in the accumulation of critical oncogenic metabolic intermediates. Notable among these intermediates are succinate, fumarate, and 2-hydroxyglutarate (2-HG), which promote activation of the HIFs signaling pathway through various mechanisms, thus inducing pseudohypoxia and facilitating tumorigenesis. SDHx mutations are prevalent in PPGLs, disrupting mitochondrial function and causing succinate accumulation, which competitively inhibits α-ketoglutarate-dependent dioxygenases. Consequently, this leads to global hypermethylation, epigenetic changes, and activation of HIFs. In FH-deficient cells, fumarate accumulation leads to protein succination, impacting cell function. FH mutations also trigger metabolic reprogramming towards glycolysis and lactate synthesis. IDH1/2 mutations generate D-2HG, inhibiting α-ketoglutarate-dependent dioxygenases and stabilizing HIFs. Similarly, MDH2 mutations are associated with HIF stability and pseudohypoxic response. Understanding the intricate relationship between metabolic enzyme mutations in the TCA cycle and pseudohypoxic signaling is crucial for unraveling the pathogenesis of PPGLs and developing targeted therapies. This knowledge enhances our comprehension of the pivotal role of cellular metabolism in PPGLs and holds implications for potential therapeutic advancements.
2023-09-17 | Pheochromocytoma and paraganglioma in children and adolescents
Pheochromocytoma (PPC) and paraganglioma (PGL) are the tumors that rarely occur in the pediatric population (PPGL). Both originate from chromaffin cells, pheochromocytoma is localized in the adrenal gland, whereas paragangliomas are regarded as the tumors present in other localizations, from head to the pelvis. The clinical image is characterized by the presence of the sustained hypertension, headaches, sweating, palpitations. The symptoms are caused by the catecholamine secretion or are related to tumor mass pressure on different organs. The catecholamines and their metabolites levels in urine collection or plasma are necessary for further evaluation of the diagnosis. In pediatric population the tumors occur in multiple familial syndromes such as Multiple Endocrine type 2, Neurofibromatosis type 1, Von Hippel-Lindau syndrome, Familial Paraganglioma syndrome are related to specific mutations (SDHx, RET, VHL, NF1) leading to the characteristic phenotype. The radiological and nuclear imaging are an important part of the examination. Although CT and MR are reported to have overall good sensitivity for the tumor detection, further analysis with nuclear imaging is recommended for the specified diagnosis. Right now 68GA-DOTATATE is regarded as the tracer of choice, leading to the complex evaluation of patients with different mutations and metastatic disease. The treatment of choice is the tumor excision. Also, lately new therapeutic approaches including genetically targeted therapies are under investigation for more complex treatment of tumors with underlying genetic cause or metastatic disease. Long term follow-up after treatment to avoid recurrence or to detect it in early stadium must be performed.
2023-09-01 | Hypertensive Crisis in a Patient With a Functioning Mesenteric Paraganglioma: Dramatic Response to Octreotide Treatment
Abstract
Background/Objective
To report a dramatic and immediate clinical and biochemical response during treatment with octreotide in a patient with a functioning mesenteric paraganglioma (PGL).
Case Report
A 44-year-old woman was admitted with a severe hypertensive crisis and a blood pressure reaching 260/150 mm Hg. She was 2 months postpartum and had been previously diagnosed with pre-eclampsia. Secondary hypertension was suspected. This was confirmed by finding a 6 × 5-cm2 retroperitoneal mass located using 68-Gallium DOTA–octreotate positron emission tomography/computed tomography and a grossly elevated plasma catecholamine level of 93 000 pmol/L (normal reference range: 650-2433 pmol/L). Treatment was immediately started with high doses of long- and short-acting octreotide. After 6 weeks and before surgery, the patient was normotensive, with a blood pressure of 120/70 mm Hg and a norepinephrine level of 6000 pmol/L. The tumor resection was uneventful, and histology confirmed the diagnosis. Following the surgery, the patient remained normotensive without any medications.
Discussion
PGLs and pheochromocytomas are neuroendocrine tumors, and most have receptors for octreotide. This case and another patient previously reported responded dramatically to treatment with a high dose of octreotide. Earlier reports of patients failing to respond are likely to have been the result of using a smaller octreotide dose.
Conclusion
We conclude that high doses of short- and long-acting octreotide are valuable in severely hypertensive patients. Our experience suggests that octreotide is of value in other patients with PGLs and pheochromocytomas. The response is rapid, sustained, effective, and with minimal reported side effects. To the best of our knowledge, this is the first report of a hypertensive crisis in a functional mesenteric PGL.
2023-06-08 | HIF and MYC signaling in adrenal neoplasms of the neural crest: implications for pediatrics
Pediatric neural crest-derived adrenal neoplasms include neuroblastoma and pheochromocytoma. Both entities are associated with a high degree of clinical heterogeneity, varying from spontaneous regression to malignant disease with poor outcome. Increased expression and stabilization of HIF2α appears to contribute to a more aggressive and undifferentiated phenotype in both adrenal neoplasms, whereas MYCN amplification is a valuable prognostic marker in neuroblastoma. The present review focuses on HIF- and MYC signaling in both neoplasms and discusses the interaction of associated pathways during neural crest and adrenal development as well as potential consequences on tumorigenesis. Emerging single-cell methods together with epigenetic and transcriptomic analyses provide further insights into the importance of a tight regulation of HIF and MYC signaling pathways during adrenal development and tumorigenesis. In this context, increased attention to HIF-MYC/MAX interactions may also provide new therapeutic options for these pediatric adrenal neoplasms.
small molecules
2024-09-25 | Current views on the role of HIF-2α in the pathogenesis and syndromic presentation of pheochromocytoma and paraganglioma
Pathogenic variants (PVs) in EPAS1, which encodes hypoxia-inducible factor-2α (HIF-2α), could be the underlying genetic cause of about 3%-6% of pheochromocytoma and paragangliomas (PPGLs). EPAS1-related PPGLs may occur as isolated tumors or as part of Pacak-Zhuang Syndrome (PZS) with two or more of a triad of PPGL, polycythemia, and somatostatinoma. HIF-2α plays a critical role in the regulation of the cellular hypoxia pathway. When a gain-of-function PV is acquired, HIF-2α evades steady-state hydroxylation by the prolyl hydroxylase type 2 (PHD2), which accelerates von Hippel-Lindau (VHL)-mediated proteasomal degradation. In this situation, HIF-2α is stabilized and can translocate to the nucleus, inducing the expression of several genes involved in tumorigenesis. This leads to the development of PPGL and other manifestations of PZS. EPAS1-related PPGLs usually occur in the second or third decade of life, more frequently in females, and are usually multiple, adrenal and extra-adrenal, and norepinephrine-secreting. In addition, these tumors carry an increased metastatic potential and have been reported with metastatic disease in up to 30% of cases. While polycythemia is fairly common in PZS, somatostatinomas are rare. It has been suggested that the character of the acquired PV in EPAS1, which affects its binding to PHD2, correlates with certain phenotypes in PZS. PVs in EPAS1 that have been found in related sporadic PPGLs have also been associated with hypoxic conditions including cyanotic congenital heart disease, hemoglobinopathies and high altitude. Understanding the hypoxia pathway and its role in the pathogenesis of PPGL may open a new avenue for developing effective therapies for these tumors. Indeed, one of these therapies is Belzutifan, a HIF-2α inhibitor that is being tested in the treatment of metastatic PPGLs.
2023-10-05 | The connection between tricarboxylic acid cycle enzyme mutations and pseudohypoxic signaling in pheochromocytoma and paraganglioma
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells, holding significant clinical importance due to their capacity for excessive catecholamine secretion and associated cardiovascular complications. Roughly 80% of cases are associated with genetic mutations. Based on the functionality of these mutated genes, PPGLs can be categorized into distinct molecular clusters: the pseudohypoxia signaling cluster (Cluster-1), the kinase signaling cluster (Cluster-2), and the WNT signaling cluster (Cluster-3). A pivotal factor in the pathogenesis of PPGLs is hypoxia-inducible factor-2α (HIF2α), which becomes upregulated even under normoxic conditions, activating downstream transcriptional processes associated with pseudohypoxia. This adaptation provides tumor cells with a growth advantage and enhances their ability to thrive in adverse microenvironments. Moreover, pseudohypoxia disrupts immune cell communication, leading to the development of an immunosuppressive tumor microenvironment. Within Cluster-1a, metabolic perturbations are particularly pronounced. Mutations in enzymes associated with the tricarboxylic acid (TCA) cycle, such as succinate dehydrogenase (SDHx), fumarate hydratase (FH), isocitrate dehydrogenase (IDH), and malate dehydrogenase type 2 (MDH2), result in the accumulation of critical oncogenic metabolic intermediates. Notable among these intermediates are succinate, fumarate, and 2-hydroxyglutarate (2-HG), which promote activation of the HIFs signaling pathway through various mechanisms, thus inducing pseudohypoxia and facilitating tumorigenesis. SDHx mutations are prevalent in PPGLs, disrupting mitochondrial function and causing succinate accumulation, which competitively inhibits α-ketoglutarate-dependent dioxygenases. Consequently, this leads to global hypermethylation, epigenetic changes, and activation of HIFs. In FH-deficient cells, fumarate accumulation leads to protein succination, impacting cell function. FH mutations also trigger metabolic reprogramming towards glycolysis and lactate synthesis. IDH1/2 mutations generate D-2HG, inhibiting α-ketoglutarate-dependent dioxygenases and stabilizing HIFs. Similarly, MDH2 mutations are associated with HIF stability and pseudohypoxic response. Understanding the intricate relationship between metabolic enzyme mutations in the TCA cycle and pseudohypoxic signaling is crucial for unraveling the pathogenesis of PPGLs and developing targeted therapies. This knowledge enhances our comprehension of the pivotal role of cellular metabolism in PPGLs and holds implications for potential therapeutic advancements.
2023-09-17 | Pheochromocytoma and paraganglioma in children and adolescents
Pheochromocytoma (PPC) and paraganglioma (PGL) are the tumors that rarely occur in the pediatric population (PPGL). Both originate from chromaffin cells, pheochromocytoma is localized in the adrenal gland, whereas paragangliomas are regarded as the tumors present in other localizations, from head to the pelvis. The clinical image is characterized by the presence of the sustained hypertension, headaches, sweating, palpitations. The symptoms are caused by the catecholamine secretion or are related to tumor mass pressure on different organs. The catecholamines and their metabolites levels in urine collection or plasma are necessary for further evaluation of the diagnosis. In pediatric population the tumors occur in multiple familial syndromes such as Multiple Endocrine type 2, Neurofibromatosis type 1, Von Hippel-Lindau syndrome, Familial Paraganglioma syndrome are related to specific mutations (SDHx, RET, VHL, NF1) leading to the characteristic phenotype. The radiological and nuclear imaging are an important part of the examination. Although CT and MR are reported to have overall good sensitivity for the tumor detection, further analysis with nuclear imaging is recommended for the specified diagnosis. Right now 68GA-DOTATATE is regarded as the tracer of choice, leading to the complex evaluation of patients with different mutations and metastatic disease. The treatment of choice is the tumor excision. Also, lately new therapeutic approaches including genetically targeted therapies are under investigation for more complex treatment of tumors with underlying genetic cause or metastatic disease. Long term follow-up after treatment to avoid recurrence or to detect it in early stadium must be performed.
2023-09-01 | Hypertensive Crisis in a Patient With a Functioning Mesenteric Paraganglioma: Dramatic Response to Octreotide Treatment
Abstract
Background/Objective
To report a dramatic and immediate clinical and biochemical response during treatment with octreotide in a patient with a functioning mesenteric paraganglioma (PGL).
Case Report
A 44-year-old woman was admitted with a severe hypertensive crisis and a blood pressure reaching 260/150 mm Hg. She was 2 months postpartum and had been previously diagnosed with pre-eclampsia. Secondary hypertension was suspected. This was confirmed by finding a 6 × 5-cm2 retroperitoneal mass located using 68-Gallium DOTA–octreotate positron emission tomography/computed tomography and a grossly elevated plasma catecholamine level of 93 000 pmol/L (normal reference range: 650-2433 pmol/L). Treatment was immediately started with high doses of long- and short-acting octreotide. After 6 weeks and before surgery, the patient was normotensive, with a blood pressure of 120/70 mm Hg and a norepinephrine level of 6000 pmol/L. The tumor resection was uneventful, and histology confirmed the diagnosis. Following the surgery, the patient remained normotensive without any medications.
Discussion
PGLs and pheochromocytomas are neuroendocrine tumors, and most have receptors for octreotide. This case and another patient previously reported responded dramatically to treatment with a high dose of octreotide. Earlier reports of patients failing to respond are likely to have been the result of using a smaller octreotide dose.
Conclusion
We conclude that high doses of short- and long-acting octreotide are valuable in severely hypertensive patients. Our experience suggests that octreotide is of value in other patients with PGLs and pheochromocytomas. The response is rapid, sustained, effective, and with minimal reported side effects. To the best of our knowledge, this is the first report of a hypertensive crisis in a functional mesenteric PGL.
2023-06-08 | HIF and MYC signaling in adrenal neoplasms of the neural crest: implications for pediatrics
Pediatric neural crest-derived adrenal neoplasms include neuroblastoma and pheochromocytoma. Both entities are associated with a high degree of clinical heterogeneity, varying from spontaneous regression to malignant disease with poor outcome. Increased expression and stabilization of HIF2α appears to contribute to a more aggressive and undifferentiated phenotype in both adrenal neoplasms, whereas MYCN amplification is a valuable prognostic marker in neuroblastoma. The present review focuses on HIF- and MYC signaling in both neoplasms and discusses the interaction of associated pathways during neural crest and adrenal development as well as potential consequences on tumorigenesis. Emerging single-cell methods together with epigenetic and transcriptomic analyses provide further insights into the importance of a tight regulation of HIF and MYC signaling pathways during adrenal development and tumorigenesis. In this context, increased attention to HIF-MYC/MAX interactions may also provide new therapeutic options for these pediatric adrenal neoplasms.
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Drug Discovery Landscape
2 orphan drug designations for Sporadic pheochromocytoma/secreting paraganglioma, including 1 approved therapy.
2 orphan drug designations for Sporadic pheochromocytoma/secreting paraganglioma, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
iobenguane sulfate I-123 | small molecules | FDA | — | Brogan Pharmaceuticals, Inc. |
Iobenguane Sulfate I 131 | small molecules | FDA | Approved | University of Michigan |
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