Succinate Dehydrogenase Deficiency Research Articles

GASTRIC GASTROINTESTINAL STROMAL TUMOR WITH SUCCINATE DEHYDROGENASE B DEFICIENCY: CLINICAL CASE

Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors found in the gastrointestinal tract, constituting a diverse group of c-Kit positive mesenchymal (stromal or connective tissue) tumors. Their development is primarily associated with mutations in the c-Kit proto-oncogene, leading to structural alterations in the type III transmembrane tyrosine kinase receptor (Kit). This receptor is crucial for regulating mitotic activity and cell differentiation. The activation of the Kit-receptor in tumor cells is identified through the expression of the immunohistochemical marker CD 117 (tyrosine kinase receptor protein), with approximately 80-90% of GISTs testing positive for CD 117. The objective of our study is to improve the diagnosis and treatment of gastrointestinal stromal tumors. The clinical case underscores the challenge of diagnosing gastrointestinal stromal tumors (GISTs) due to the absence of specific and definitive symptoms. In this instance, only radical surgical intervention facilitated an accurate diagnosis. Given the location of the tumor in the pyloric part of the gastric submucosal layer, a reliable biopsy during video esophagogastroduodenoscopy was unfeasible, as the gastric mucosa above the tumor appeared unaffected. Consequently, surgery with complete tumor excision and subsequent pathohistological and immunohistochemical analysis emerged as the primary diagnostic and therapeutic approach. These investigations confirmed the presence of a gastrointestinal stromal tumor of the stomach with succinate dehydrogenase B deficiency. In approximately 80% of GIST cases, succinate dehydrogenase deficiency plays a pivotal role. The absence of succinate dehydrogenase disrupts the Krebs cycle, leading to an accumulation of succinate, an oncometabolite that fuels carcinogenesis. Such tumors exhibit distinctive clinical characteristics, prognostic outcomes, and responsiveness to targeted therapies. Succinate dehydrogenase deficiency can arise from mutations or epigenomic alterations affecting gene expression. Notably, mutations or epigenomic disruptions in any succinate dehydrogenase subunit inevitably result in the loss of subunit B expression.

Multiple and hereditary renal tumors: a review for radiologists

80% of renal carcinomas (RC) are diagnosed incidentally by imaging. 2–4% of "sporadic" multifocality and 5–8% of hereditary syndromes are accepted, probably with underestimation. Multifocality, young age, familiar history, syndromic data, and certain histologies lead to suspicion of hereditary syndrome. Each tumor must be studied individually, with a multidisciplinary evaluation of the patient. Nephron-sparing therapeutic strategies and a radioprotective diagnostic approach are recommended.Relevant data for the radiologist in major RC hereditary syndromes are presented: von-Hippel-Lindau, Chromosome-3 translocation, BRCA-associated protein-1 mutation, RC associated with succinate dehydrogenase deficiency, PTEN, hereditary papillary RC, Papillary thyroid cancer- Papillary RC, Hereditary leiomyomatosis and RC, Birt-Hogg-Dubé, Tuberous sclerosis complex, Lynch, Xp11.2 translocation/TFE3 fusion, Sickle cell trait, DICER1 mutation, Hereditary hyperparathyroidism and jaw tumor, as well as the main syndromes of Wilms tumor predisposition.The concept of "non-hereditary" familial RC and other malignant and benign entities that can present as multiple renal lesions are discussed.

Peak study: A phase 3, randomized, open-label multicenter clinical study of bezuclastinib (CGT9486) and sunitinib in combination versus sunitinib in patients with gastrointestinal stromal tumors (GIST).

TPS766 Background: Imatinib is the worldwide standard for first-line therapy of advanced KIT-mutant GIST. However, secondary resistance mutations in the KIT ATP-binding domain (exons 13, 14), activation loop (exons 17, 18), or both develop and result in loss of imatinib-sensitivity. While no single tyrosine kinase inhibitor (TKI) inhibits all KIT mutations, the combination of bezuclastinib + sunitinib targets commonly occurring primary (exons 9, 11) and secondary (exons 13, 14, 17, and 18) KIT mutations. In a Phase 1/2 clinical study, pts with relapsed and/or refractory GIST and a median of 3 prior lines of therapy treated with bezuclastinib + sunitinib (n=15) experienced clinical benefit and an acceptable safety profile, warranting further evaluation in a randomized trial. Methods: Peak (NCT05208047) is a global, randomized, open-label, multi-part Phase 3 study evaluating the efficacy and safety of bezuclastinib + sunitinib versus sunitinib as second-line treatment in adult pts who were intolerant to imatinib or whose tumors had imatinib-resistance. The lead-in portion, to test a new formulation of bezuclastinib, (Part 1) has completed enrollment. Based upon PK and safety, a dose of bezuclastinib 600 mg QD + sunitinib 37.5 mg QD has been determined for Part 2 of the Peak study. Part 2 will enroll ~388 pts to be randomized (1:1) to bezuclastinib 600 mg QD + sunitinib 37.5 mg QD or sunitinib 37.5 mg QD alone. Key inclusion: >1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1, Eastern Cooperative Oncology Group Performance Status 0-2, adequate organ function, and prior imatinib therapy (no other prior therapy). Key exclusion: PDGFR mutations or succinate dehydrogenase deficiency, clinically significant cardiac disease, and use of strong CYP3A4 inhibitors or inducers. The primary endpoint is progression-free survival (PFS) confirmed by blinded independent central review per mRECIST v1.1. Additional efficacy (including overall survival and objective response rate) and safety endpoints will be evaluated. Clinical trial information: NCT05208047 .

Molecular features of gastrointestinal stromal tumors “wild-type” (<i>KIT/PDGFRA</i> WT)

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Their main features are the expression of CD117 (KIT) and mutations of KIT or PDGFRA in 85 % of patients. however, 10–15 % of adult GIST and 85 % of pediatric GIST do not have KIT/PDGFRA mutations (KIT/PDGFRA WT GIST or “wild-type” GIST). The prognosis and clinical course of these tumors and GIST with KIT/PDGFRA mutations differ. “Wild-type” GIST are quite heterogeneous group of tumors in terms of clinical phenotype, genetic etiology, and molecular pathways. Gastrointestinal stromal tumors are divided into SDH-deficient and SDH-competent based on the succinate dehydrogenase (SDH) complex. SDH-deficient GIST occur predominantly in children and young patients with Carney–Stratakis syndrome and Carney triad; there are also sporadic tumors. More than half of SDH-deficient GIST contain mutations in SDHA, SDHB, SDHD or SDHC, while the rest are caused by hypermethylation of the SDHC promoter. SDH-competent “wild-type” GIST include tumors with BRAF, RAS, or NF1 mutations that activate the RAS-RAF-MAPK pathway and KIT/PDGFRA/SDH/RAS-P WT GIST subtype or “quadruple wild type” GIST. The genomic profiles of these tumors and GIST with KIT/PDGFRA mutation or SDH deficiency differ significantly. One of the features of “quadruple wild type” GIST is activation of the FGFR (fibroblast growth factor receptors) signaling pathway due to chimeric FGFR, FGFR mutations, or overexpression of FGF (fibroblast growth factor). Another feature is chimeric genes containing fragments of NTRK, BRAF, FGFR and other genes that behave as oncogene drivers. In “quadruple wild-type” GIST the somatic mutations in TP53, MAX, MEN1, CTNND2, CHD4, ARIDIA and other genes were revealed as well as in the cell cycle genes RB1, CDK4, CDKN1B. There is no specific treatment for patients with “wild-type” GIST; the choice of drug is determined by the genetic disorder. There is a need to improve our understanding of the molecular mechanisms underlying the different GIST subtypes to develop more effective therapeutic approaches.

Succinate dehydrogenase is essential for epigenetic and metabolic homeostasis in hearts.

A hallmark of heart failure is a metabolic switch away from fatty acids β-oxidation (FAO) to glycolysis. Here, we show that succinate dehydrogenase (SDH) is required for maintenance of myocardial homeostasis of FAO/glycolysis. Mice with cardiomyocyte-restricted deletion of subunit b or c of SDH developed a dilated cardiomyopathy and heart failure. Hypertrophied hearts displayed a decrease in FAO, while glucose uptake and glycolysis were augmented, which was reversed by enforcing FAO fuels via a high-fat diet, which also improved heart failure of mutant mice. SDH-deficient hearts exhibited an increase in genome-wide DNA methylation associated with accumulation of succinate, a metabolite known to inhibit DNA demethylases, resulting in changes of myocardial transcriptomic landscape. Succinate induced DNA hypermethylation and depressed the expression of FAO genes in myocardium, leading to imbalanced FAO/glycolysis. Inhibition of succinate by α-ketoglutarate restored transcriptional profiles and metabolic disorders in SDH-deficient cardiomyocytes. Thus, our findings reveal the essential role for SDH in metabolic remodeling of failing hearts, and highlight the potential of therapeutic strategies to prevent cardiac dysfunction in the setting of SDH deficiency.

Diagnosis, Genetics, and Management of 24 Patients With Cardiac Paragangliomas: Experience From a Single Center.

Paragangliomas located within the pericardium represent a rare yet challenging clinical situation. The current analysis aimed to describe the clinical characteristics of cardiac paragangliomas, with emphasis on the diagnostic approach, genetic background, and multidisciplinary management. Twenty-four patients diagnosed with cardiac paraganglioma (PGL) in Peking Union Medical College Hospital, Beijing, China, between 2003 and 2021 were identified. Clinical data was collected from medical record. Genetic screening and succinate dehydrogenase subunit B immunohistochemistry were performed in 22 patients. The median age at diagnosis was 38 years (range 11-51 years), 8 patients (33%) were females, and 4 (17%) had familial history. Hypertension and/or symptoms related to catecholamine secretion were present in 22 (92%) patients. Excess levels of catecholamines and/or metanephrines were detected in 22 (96%) of the 23 patients who have completed biochemical testing. Cardiac PGLs were localized with 131I-metaiodobenzylguanidine scintigraphy in 11/22 (50%), and 99mTc-hydrazinonicotinyl-tyr3-octreotide scintigraphy in 24/24 (100%) patients. Genetic testing identified germline SDHx mutations in 13/22 (59%) patients, while immunohistochemistry revealed succinate dehydrogenase (SDH) deficiency in tumors from 17/22 (77%) patients. All patients were managed by a multidisciplinary team through medical preparation, surgery, and follow-up. Twenty-three patients received surgical treatment and perioperative death occurred in 2 cases. Overall, 21 patients were alive at follow-up (median 7.0 years, range 0.6-18 years). Local recurrence or metastasis developed in 3 patients, all of whom had SDH-deficient tumors. Cardiac PGLs can be diagnosed based on clinical manifestations, biochemical tests, and appropriate imaging studies. Genetic screening, multidisciplinary approach, and long-term follow-up are crucial in the management of this disease.

Pyruvate transamination and NAD biosynthesis enable proliferation of succinate dehydrogenase-deficient cells by supporting aerobic glycolysis

Succinate dehydrogenase (SDH) is the mitochondrial enzyme converting succinate to fumarate in the tricarboxylic acid (TCA) cycle. SDH acts as a tumor suppressor with germline loss-of-function mutations in its encoding genes predisposing to aggressive familial neuroendocrine and renal cancer syndromes. Lack of SDH activity disrupts the TCA cycle, imposes Warburg-like bioenergetic features, and commits cells to rely on pyruvate carboxylation for anabolic needs. However, the spectrum of metabolic adaptations enabling SDH-deficient tumors to cope with a dysfunctional TCA cycle remains largely unresolved. By using previously characterized Sdhb-deleted kidney mouse cells, here we found that SDH deficiency commits cells to rely on mitochondrial glutamate-pyruvate transaminase (GPT2) activity for proliferation. We showed that GPT2-dependent alanine biosynthesis is crucial to sustain reductive carboxylation of glutamine, thereby circumventing the TCA cycle truncation determined by SDH loss. By driving the reductive TCA cycle anaplerosis, GPT2 activity fuels a metabolic circuit maintaining a favorable intracellular NAD+ pool to enable glycolysis, thus meeting the energetic demands of SDH-deficient cells. As a metabolic syllogism, SDH deficiency confers sensitivity to NAD+ depletion achieved by pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway. Beyond identifying an epistatic functional relationship between two metabolic genes in the control of SDH-deficient cell fitness, this study disclosed a metabolic strategy to increase the sensitivity of tumors to interventions limiting NAD availability.

Tumores renales múltiples y hereditarios. Revisión por y para radiólogos

80% of renal carcinomas (RC) are diagnosed incidentally by imaging. 2-4% of “sporadic” multifocality and 5-8% of hereditary syndromes are accepted, probably with underestimation. Multifocality, young age, familiar history, syndromic data, and certain histologies lead to suspicion of hereditary syndrome. Each tumor must be studied individually, with a multidisciplinary evaluation of the patient. Nephron-sparing therapeutic strategies and a radioprotective diagnostic approach are recommended.Relevant data for the radiologist in major RC hereditary syndromes are presented: von-Hippel-Lindau, Chromosome-3 translocation, BRCA-associated protein-1 mutation, RC associated with succinate dehydrogenase deficiency, PTEN, hereditary papillary RC, Papillary thyroid cancer- Papillary RC, Hereditary leiomyomatosis and RC, Birt-Hogg-Dubé, Tuberous sclerosis complex, Lynch, Xp11.2 translocation/TFE3 fusion, Sickle cell trait, DICER1 mutation, Hereditary hyperparathyroidism and jaw tumor, as well as the main syndromes of Wilms tumor predisposition.The concept of “non-hereditary” familial RC and other malignant and benign entities that can present as multiple renal lesions are discussed.

SDH deficiency is very common in carotid body paragangliomas: Genetic counseling and testing should be offered to all patients.

Collectively, germline pathogenic variants in succinate dehydrogenase (SDH) genes are the most common cause of hereditary paragangliomas. Loss of immunohistochemical expression of SDHB protein (termed SDH deficiency) occurs whenever there is biallelic inactivation of any SDH gene. We sought to estimate the prevalence of SDH deficiency in patients with carotid body paragangliomas. We identified all carotid body paragangliomas that had undergone surgical excision at our institution over the last 30 years. If SDHB immunohistochemistry was not performed at the time of excision, it was performed on archived material. There were 64 carotid body paragangliomas identified in the 62 patients. Two-thirds of the patients were female, and 43 (67%) were SDH-deficient. Up to two-thirds of all carotid body paragangliomas are associated with SDH deficiency. Therefore, genetic testing and counseling should be offered to all patients with carotid body paragangliomas, regardless of age or family history.

PD17-01 THE IMPACT OF LOSS AND MUTATION OF MITOCHONDRIAL DNA ON ONCOMETABOLITE ACCUMULATION IN PATIENT-DERIVED FUMARATE HYDRATASE-DEFICIENT RENAL TUMOR CELL LINES

You have accessJournal of UrologyCME1 Apr 2023PD17-01 THE IMPACT OF LOSS AND MUTATION OF MITOCHONDRIAL DNA ON ONCOMETABOLITE ACCUMULATION IN PATIENT-DERIVED FUMARATE HYDRATASE-DEFICIENT RENAL TUMOR CELL LINES Bhargav Arimilli, Daniel Crooks, Ye Yang, Youfeng Yang, Cathy Vocke, Christopher Ricketts, Mark Ball, Teresa Fan, Andrew Lane, and W. Marston Linehan Bhargav ArimilliBhargav Arimilli More articles by this author , Daniel CrooksDaniel Crooks More articles by this author , Ye YangYe Yang More articles by this author , Youfeng YangYoufeng Yang More articles by this author , Cathy VockeCathy Vocke More articles by this author , Christopher RickettsChristopher Ricketts More articles by this author , Mark BallMark Ball More articles by this author , Teresa FanTeresa Fan More articles by this author , Andrew LaneAndrew Lane More articles by this author , and W. Marston LinehanW. Marston Linehan More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003272.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant cancer syndrome characterized by mutations in the fumarate hydratase gene (FH). We recently reported the discovery of mutations and loss of mitochondrial DNA (mtDNA) in FH-deficient renal tumors and tumor-derived cell lines. Mitochondrial alterations in FH-deficient tumor-derived cell lines ranged from inactivating mutations in mitochondrial Complex I and Complex III subunits to complete loss of mtDNA in two tumor cell lines. The goal of the present study was to characterize the impact of mtDNA mutations on the oncometabolites fumarate and succinate in FH-deficient renal tumor cell lines. METHODS: We performed stable isotope-resolved metabolomics (SIRM) with 13C5,15N2-glutamine tracer on five FH-deficient patient-derived tumor cell lines, and utilized ion chromatography coupled with ultra-high resolution Orbitrap-based mass spectrometry (UHR-ICMS) and NMR spectroscopy to determine the abundance and isotopic labeling pattern of fumarate and its precursors in polar extracts obtained from the tumor cells. RESULTS: We found that several of the FH-deficient tumor cell lines showed elevated succinate levels, with a 13C labeling pattern that was consistent with oxidative production of succinate from glutamine. In contrast, fumarate 13C labeling patterns in these same cell lines was consistent with reductive carboxylation of glutamine and formation of fumarate from the urea cycle and purine biosynthesis, suggesting a deficiency of succinate dehydrogenase (Complex II) activity in the cells. UHR-ICMS analysis of FH-/- cells labeled with 13C1-glutamine confirmed 13C labeling of the purine biosynthetic intermediate adenylosuccinate via reductive carboxylation of glutamine, giving rise to 13C1-fumarate, and this 13C label was localized to the carboxylate carbon of fumarate using an HMBC NMR experiment. CONCLUSIONS: We have uncovered additional lesions in the TCA cycle in patient-derived HLRCC cell lines, giving rise to accumulation of the oncometabolite succinate. These data highlight the metabolic heterogeneity that is observed in genetically-defined human tumors. Source of Funding: NIH NIH MRSP © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e495 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Bhargav Arimilli More articles by this author Daniel Crooks More articles by this author Ye Yang More articles by this author Youfeng Yang More articles by this author Cathy Vocke More articles by this author Christopher Ricketts More articles by this author Mark Ball More articles by this author Teresa Fan More articles by this author Andrew Lane More articles by this author W. Marston Linehan More articles by this author Expand All Advertisement PDF downloadLoading ...

SDHx mutation and pituitary adenoma: can in vivo 1H-MR spectroscopy unravel the link?

Germline mutations in genes encoding succinate dehydrogenase (SDH) are frequently involved in pheochromocytoma/paraganglioma (PPGL) development and were implicated in patients with the '3PAs' syndrome (associating pituitary adenoma (PA) and PPGL) and with isolated PA. However, the causality link between SDHx mutation and PA remains difficult to establish and in vivo tools for detecting hallmarks of SDH deficiency are scarce. Proton magnetic resonance spectroscopy (1H-MRS) can detect succinate in vivo as a biomarker of SDHx mutations in PGL. The objective of this study was to demonstrate the causality link between PA and SDH-deficiency in vivo using 1H-MRS as a novel non-invasive tool for succinate detection in PA. Three SDHx-mutated patients suffering from a PPGL and a macroprolactinoma and one patient with an apparently sporadic non-functioning pituitary macroadenoma underwent MRI examination at 3 T. An optimized 1H-MRS semi-LASER sequence (TR = 2500 ms, TE = 144 ms) was employed for the detection of succinate in vivo. Succinate and choline containing compounds were identified in the MR spectra as single resonances at 2.44 and 3.2 ppm, respectively. Choline compounds were detected in all the tumors (3 PGL and 4 PAs), while a succinate peak was only observed in the 3 macroprolactinomas and the 3 PGL of SDHx-mutated patients, demonstrating SDH deficiency in these tumors. In conclusion, detection of succinate by 1H-MRS as a hallmark of SDH deficiency in vivo is feasible in PA, laying the groundwork for a better understanding of the biological link between SDHx mutations and the development of these tumors.

Bladder paraganglioma, gastrointestinal stromal tumor, and SDHB germline mutation in a patient with Carney-Stratakis syndrome: A case report and literature review.

Carney-Stratakis syndrome (CSS) is a rare dyad of paraganglioma (PGL)/pheochromocytoma (PHEO) and gastrointestinal stromal tumor (GIST). PGLs are neuroendocrine tumors of neural crest origin which are mostly found in the head, neck, and retroperitoneal space. GISTs are the most common mesenchymal tumors of the digestive tract, usually caused by KIT/PDGFRA mutations. Here, we reported a case of CSS with unusual bladder PGL and succinate dehydrogenase (SDH) deficient GIST due to a germline mutation in SDH-subunit B (SDHB) gene. A 39-year-old female patient initially diagnosed with gastric GIST and isolated pelvic metastasis was eventually found to be CSS with bladder PGL and SDH-deficient GIST after surgery. This patient underwent resection of gastric and bladder tumors, and postoperative pathology confirmed the diagnosis of CSS. According to the next-generation sequencing (NGS), the patient carried a germline mutation in the SDHB gene, which was the cause of the disorder. The patient had no tumor recurrence with regular follow-up in 10 months. CSS is an autosomal genetic disorder with no gender difference in incidence, and PGLs are more frequent than GISTs. SDH germline mutation is the molecular biological mechanism of CSS while the most common type is SDHB mutation. The unique mechanism of tumorigenesis including hypoxia and hypermethylation caused by SDH deficiency renders target therapy with tyrosine kinase inhibitors ineffective, therefore complete surgical resection is the optimal treatment in the absence of tumor metastases.

Upregulation of Succinate Dehydrogenase (SDHA) Contributes to Enhanced Bioenergetics of Ovarian Cancer Cells and Higher Sensitivity to Anti-Metabolic Agent Shikonin.

Simple SummaryIn recent years, targeting tumor specific metabolism has gained an interest as a promising therapeutic strategy. We discovered that the overexpression of mitochondrial enzyme succinate dehydrogenase (SDHA) is highly prevalent in ovarian carcinoma patients and contributes to elevated mitochondrial metabolism in ovarian tumor models. The SDHA overexpressing tumor cells are highly metabolically active, relying on both glycolysis and oxidative phosphorylation in mitochondria to meet their energy requirements. Further, we found that those cells are particularly vulnerable to deprivation of essential nutrients such as glucose and glutamine, which led to a substantial reduction of ATP yield. Lastly, we identified an anti-metabolic compound shikonin, which demonstrated a potent anti-tumor efficacy against SDHA overexpressing ovarian cancer cells. Overall, we strive to advance scientific knowledge by uncovering the previously unappreciated role of SDHA in reprogramming of ovarian cancer metabolism, which holds untapped opportunities for therapeutic intervention.We discovered that the overexpression of mitochondrial enzyme succinate dehydrogenase (SDHA) is particularly prevalent in ovarian carcinoma and promotes highly metabolically active phenotype. Succinate dehydrogenase deficiency has been previously studied in some rare disorders. However, the role of SDHA upregulation and its impact on ovarian cancer metabolism has never been investigated, emphasizing the need for further research. We investigated the functional consequences of SDHA overexpression in ovarian cancer. Using proteomics approaches and biological assays, we interrogated protein content of metabolic pathways, cell proliferation, anchorage-independent growth, mitochondrial respiration, glycolytic function, and ATP production rates in those cells. Lastly, we performed a drug screening to identify agents specifically targeting the SDHA overexpressing tumor cells. We showed that SDHA overexpressing cells are characterized by enhanced energy metabolism, relying on both glycolysis and oxidative phosphorylation to meet their energy needs. In addition, SDHA-high phenotype was associated with cell vulnerability to glucose and glutamine deprivation, which led to a substantial reduction of ATP yield. We also identified an anti-metabolic compound shikonin with a potent efficacy against SDHA overexpressing ovarian cancer cells. Our data underline the unappreciated role of SDHA in reprogramming of ovarian cancer metabolism, which represents a new opportunity for therapeutic intervention.

GIST avancées : quels traitements en 2022 ?

Gastrointestinal stromal tumors (GIST) are rare digestive tumors. Activating KIT mutations are the most common molecular alteration in these patients, identified in approximately 70% of cases, followed by PDGFRA mutations (10-15%), of which the D842V mutation accounts for most cases. Succinate dehydrogenase (SDH) deficiency and alterations involving NF1, BRAFV600E, RAS or NTRK genes are rare molecular subgroups. In advanced GIST, treatment is based on tyrosine kinase inhibitors, including imatinib, which has been the standard first-line treatment since the early 2000s, with sunitinib and regorafenib as second- and third-line standards, respectively. Two new compounds have recently been evaluated in patients with advanced GIST. Ripretinib has become the validated fourth-line therapy for patients with KIT or PDGFRA non-D842V mutations, and avapritinib has been shown to be effective in patients with D842V mutations who were previously resistant to validated treatments. Avapritinib is now the recommended first-line treatment in this subgroup and may represent an additional option, whose place remains to be clarified, in pre-treated patients without D842V mutations. Specific treatments are available or under evaluation for some rare subgroups, and new therapeutic strategies are likely to further improve the management of advanced GIST in the coming years. This overview summarizes the results of recent trials and the place of these new molecules, as well as the main strategies under development for advanced GIST.

Serum fatty acid profiling in patients with SDHx mutations: New advances on cellular metabolism in SDH deficiency

Apart from the oncometabolite succinate, little studies have appeared on extra-mitochondrial pathways in Succinate Dehydrogenase (SDH) genetic deficiency. The role of NADH/NAD+ redox status and dependent pathways was recently emphasized. Therein, fatty acid (FA) metabolism data were collected here in 30 patients with a loss of function (LOF) variant in one SDHx gene (either with a pheochromocytoma/paraganglioma (PPGL) or asymptomatic) and in 22 wild-type SDHx controls (with PPGL or asymptomatic). Blood acylcarnitines in two patients, peroxisomal biomarkers, very long-chain saturated FA (VLCFA), and C20 to C24 n-3 polyunsaturated fatty acids (PUFA), in all patients were measured by mass spectrometry. Preliminary data showed elevated even and odd long- and very long-chain acylcarnitines in two patients with a SDHB variant. In the whole series, no abnormalities were observed in biomarkers of peroxisomal β-oxidation (C27-bile acids, VLCFAs and phytanic/pristanic acids) in SDHx patients. However, an increased hexaene to pentaene PUFA ratio ([TetraHexaenoic Acid + DocosaHexaenoic Acid]/[n-3 DocosaPentaenoic Acid + EicosaPentaenoic Acid]) was noticed in patients with SDHC/SDHD variants vs patients with SDHA/SDHB variants or controls, suggesting a higher degree of unsaturation of PUFAs. Within the group with a SDHx variant, Eicosapentaenoate/Tetracosahexaenoate ratio, as an empiric index of shortening/elongation balance, discriminated patients with PPGL from asymptomatic ones. Present findings argue for stimulated elongation of saturated FAs, changes in shortening/elongation balance and desaturation rates of C20–C24 PUFAs in SDH-deficient patients with PPGL. Overall, oxidation of NADH sustained by these pathways might reflect or impact glycolytic NAD+ recycling and hence tumor proliferation.

β-Cell Succinate Dehydrogenase Deficiency Triggers Metabolic Dysfunction and Insulinopenic Diabetes.

Mitochondrial dysfunction plays a central role in type 2 diabetes (T2D); however, the pathogenic mechanisms in pancreatic β-cells are incompletely elucidated. Succinate dehydrogenase (SDH) is a key mitochondrial enzyme with dual functions in the tricarboxylic acid cycle and electron transport chain. Using samples from human with diabetes and a mouse model of β-cell–specific SDH ablation (SDHBβKO), we define SDH deficiency as a driver of mitochondrial dysfunction in β-cell failure and insulinopenic diabetes. β-Cell SDH deficiency impairs glucose-induced respiratory oxidative phosphorylation and mitochondrial membrane potential collapse, thereby compromising glucose-stimulated ATP production, insulin secretion, and β-cell growth. Mechanistically, metabolomic and transcriptomic studies reveal that the loss of SDH causes excess succinate accumulation, which inappropriately activates mammalian target of rapamycin (mTOR) complex 1–regulated metabolic anabolism, including increased SREBP-regulated lipid synthesis. These alterations, which mirror diabetes-associated human β-cell dysfunction, are partially reversed by acute mTOR inhibition with rapamycin. We propose SDH deficiency as a contributing mechanism to the progressive β-cell failure of diabetes and identify mTOR complex 1 inhibition as a potential mitigation strategy.

Succinate dehydrogenase/complex II is critical for metabolic and epigenetic regulation of T cell proliferation and inflammation.

Effective T cell-mediated immune responses require the proper allocation of metabolic resources to sustain growth, proliferation, and cytokine production. Epigenetic control of the genome also governs T cell transcriptome and T cell lineage commitment and maintenance. Cellular metabolic programs interact with epigenetic regulation by providing substrates for covalent modifications of chromatin. By using complementary genetic, epigenetic, and metabolic approaches, we revealed that tricarboxylic acid (TCA) cycle flux fueled biosynthetic processes while controlling the ratio of succinate/α-ketoglutarate (α-KG) to modulate the activities of dioxygenases that are critical for driving T cell inflammation. In contrast to cancer cells, where succinate dehydrogenase (SDH)/complex II inactivation drives cell transformation and growth, SDH/complex II deficiency in T cells caused proliferation and survival defects when the TCA cycle was truncated, blocking carbon flux to support nucleoside biosynthesis. Replenishing the intracellular nucleoside pool partially relieved the dependence of T cells on SDH/complex II for proliferation and survival. SDH deficiency induced a proinflammatory gene signature in T cells and promoted T helper 1 and T helper 17 lineage differentiation. An increasing succinate/α-KG ratio in SDH-deficient T cells promoted inflammation by changing the pattern of the transcriptional and chromatin accessibility signatures and consequentially increasing the expression of the transcription factor, PR domain zinc finger protein 1. Collectively, our studies revealed a role of SDH/complex II in allocating carbon resources for anabolic processes and epigenetic regulation in T cell proliferation and inflammation.

Functional deficiency of succinate dehydrogenase promotes tumorigenesis and development of clear cell renal cell carcinoma through weakening of ferroptosis

ABSTRACT Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal carcinomas, with high mortality and poor prognoses worldwide. Succinate dehydrogenase (SDH) consists of four nuclear-encoded subunits and it is the only complex involved in both the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). Previous studies have shown decreased SDH activity in ccRCC. However, the role and underlying molecular mechanisms of SDH in ccRCC initiation and development remain unclear. In the present study, pan-cancer analysis of SDH gene expression was analyzed and the relationship between SDH gene expression and clinicopathological parameters was assessed using different databases. cBioPortal, UACLAN, and Tumor Immune Estimation Resource (TIMER) were subsequently utilized to analyze genetic alterations, methylation, and immune cell infiltration of SDH genes in ccRCC patients. We found SDHs were significantly downregulated in ccRCC tissues and correlated with ccRCC progression. Increased methylation and high SDH promoter mutation rates may be the cause of reduced expression of SDHs in ccRCC. Moreover, the interaction network showed that SDH genes were correlated with ferroptosis-related genes. We further demonstrated that SDH inhibition dampened oxidative phosphorylation, reduced ferroptotic events, and restored ferroptotic cell death, characterized by eliminated mitochondrial ROS levels, decreased cellular ROS and diminished peroxide accumulation. Collectively, this study provides new insights into the regulatory role of SDH in the carcinogenesis and progression of ccRCC, introducing a potential target for advanced antitumor therapy through ferroptosis.

A suppressor of dioxygenase inhibition in a yeast model of SDH deficiency.

A fascinating class of familial paraganglioma (PGL) neuroendocrine tumors is driven by the loss of the tricarboxylic acid (TCA) cycle enzyme succinate dehydrogenase (SDH) resulting in succinate accumulation as an oncometabolite and other metabolic derangements. Here, we exploit a Saccharomyces cerevisiae yeast model of SDH loss where accumulating succinate, and possibly reactive oxygen species, poison a dioxygenase enzyme required for sulfur scavenging. Using this model, we performed a chemical suppression screen for compounds that relieve dioxygenase inhibition. After testing 1280 pharmaceutically active compounds, we identified meclofenoxate HCl and its hydrolysis product, dimethylaminoethanol (DMAE), as suppressors of dioxygenase intoxication in SDH-loss yeast cells. We show that DMAE acts to alter metabolism so as to normalize the succinate:2-ketoglutarate ratio, improving dioxygenase function. This study raises the possibility that oncometabolite effects might be therapeutically suppressed by drugs that rewire metabolism to reduce the flux of carbon into pathological metabolic pathways.

Taming the Wild-Type Gastrointestinal Stromal Tumor: Improved Tissue Culture.

Wild-type gastrointestinal stromal tumors (WT GIST) are most frequently characterized by succinate dehydrogenase (SDH) deficiency. Reliable ex vivo tumor models have been difficult to develop given the downstream metabolic effects of SDH deficiency. Improved tumor modeling approaches are needed to develop effective systemic treatment options for patients with WT GIST.See related article by Yebra et al., p. 187.