Diagnosis, Pathophysiology And Molecular Biology of Pheochromocytoma and Paraganglioma

嗜铬细胞瘤和副神经节瘤的诊断、病理生理学和分子生物学

• 批准号: 10266489
• 负责人: Karel Pacak
• 金额: $ 226.27万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10266489
• 关键词: 13 year old; 16 year old; Abdomen; Adrenal Gland Neoplasms; Adrenal Glands; Adrenergic Receptor; Age; Allografting; Animal Model; Apoptosis; Arrhythmia; Ascorbic Acid; Basic Science; Benign; Biochemical Markers; Biological Markers; Brown Fat; Carrier Proteins; Case-Control Studies; Catecholamines; Cause of Death; Cells; Chemistry; Child; Clinical; Clinical Trials; Collaborations; Control Groups; Data; Deoxyglucose; Development; Diagnosis; Diagnostic; Discipline of Nuclear Medicine; Disease; Emission-Computed Tomography; Endocrinologist; Epidemiology; Equilibrium; Etiology; European; Evaluation; Event; Exhibits; Failure; Family history of; Female; Functional disorder; Gene Mutation; Genes; Genetic; Genomics; Glutathione; Goals; Guidelines; Health Professional; Heart; Homeostasis; Hypertension; Image; Imaging Techniques; Immunologic Markers; Immunotherapy; Institutes; Institution; Interdisciplinary Study; International; Iron; Iron Overload; Knowledge; Laboratories; Link; Localized Disease; Location; Malignant Neoplasms; Malignant Pheochromocytoma; Mediating; Medical; Medical Genetics; Medical center; Metabolic; Metabolic Pathway; Methods; Molecular; Molecular Biology; Molecular Genetics; Monitor; Mus; Mutate; Mutation; Neoplasm Metastasis; Neuroendocrine Tumors; Neuroendocrinology; Norepinephrine; Operative Surgical Procedures; Outcome; Oxidation-Reduction; Oxidative Stress; Oxygen; PET/CT scan; Paraganglioma; Pathogenesis; Pathway interactions; Patients; Peptide Receptor; Performance; Pharmaceutical Preparations; Pharmacology; Phenotype; Pheochromocytoma; Plasma; Play; Positron-Emission Tomography; Procedures; Professional Organizations; Publishing; Radiation therapy; Radionuclide Imaging; Radionuclide therapy; Reactive Oxygen Species; Reporting; Research Personnel; Risk; SLC11A2 gene; Sinus; Societies; Somatostatin Analog Therapy; Staging; Succinate Dehydrogenase; Survival Rate; Tachyarrhythmias; Technology; Therapeutic; Time; Transferrin; Translational Research; United States National Institutes of Health; Update; X-Ray Computed Tomography; adrenal hypertension; age group; base; chemotherapy; clinical Diagnosis; clinical application; cohort; conventional therapy; cytotoxicity; driving force; fluorodeoxyglucose; follow-up; genetic disorder diagnosis; imaging approach; imaging modality; improved; in vivo; inhibitor/antagonist; ivabradine; knock-down; male; meetings; member; metabolomics; metaiodobenzylguanidine; molecular imaging; mortality; mutation carrier; noradrenergic; novel therapeutics; nuclear factor-erythroid 2; outcome forecast; oxidative DNA damage; patient oriented; patient oriented research; pediatric patients; pre-clinical; research clinical testing; single photon emission computed tomography; stomach cardia; symposium; transferrin receptor 2; tumor; tumorigenesis; working group

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

本节正在进行有关病因，流行病学，病理生理学，遗传学，诊断和治疗嗜铬细胞瘤和paraganglioma（PPGL）的研究。项目不仅包括将基础科学知识应用于临床诊断，病理生理学和治疗，还包括反向翻译研究，对临床发现的欣赏会导致基础研究人员可以在实验室中追求的新概念。 为了实现我们的目标，本节的策略基于NIH调查人员和外部医疗中心/机构之间的多学科合作。我们的部分将面向患者的组件与两个基准级组件链接在一起。目前，面向患者的成分（医学神经内分泌学）是我们假设和发现的主要驱动力。两个基准级成分（肿瘤发病机理，遗传学，化学和生物标志物以及实验性免疫疗法）首先强调，这是针对途径和靶标发现的基础研究的技术，第二，第二，将发现的发展开发到临床应用中。 PPGL的临床和遗传方面 在只有几个与SDHB突变相关病例的儿童中，PPGL很少见。先前对儿童的研究是在小型队列中进行的。这组大量的儿科患者在评估临床结果时提供了强大的数据。 38名男性和26名女性在中位年龄为13岁。大多数患者表现出去甲肾上腺素的过度分泌，最初出现73.44％的患者。在16岁的中位患者中，有70％的患者发生转移，大多数被诊断出头2年，在诊断后12 - 18年中。诊断时转移的存在对男性的存活情况有很大的负面影响，但在女性中却没有强烈的负面影响。估计的5、10和20年生存率分别为100％，97.14％和77.71％。本报告强调了与pheo/pgl相关的SDHB突变患者管理的几个重要方面。 SDHB突变载体的初始诊断评估应在5-6岁时开始，最初的锻炼重点是腹部区域。彻底的随访是在诊断后至关重要的两年，由于转移风险增加，在10 - 20年诊断中需要更频繁的随访。尽管该年龄段最早从诊断开始了5年，但我们已经表明，整体20年的预后和生存良好。 PPGL相关的临床后遗症是由儿茶酚胺分泌引起的，可能导致高血压，心律失常，多器官衰竭以及由儿茶酚胺水平升高引起的死亡。我们引入了伊瓦布拉丁（Ivabradine）是一种市售的药物，它直接在心脏中直接作用于鼻窦节点，以治疗严重的儿茶酚胺诱导的心律失常。我们还发表了一些有关Cardia PGL的全面评论以及心律不齐的治疗方法。 在另一项研究中，我们评估了SDHA基因突变患者的PPGL患者。我们的发现表明，这些肿瘤可以提早发生，并且在肾上腺外部位置，表现出积极的态度，并且倾向于在短时间内发展转移性疾病。我们的患者都没有PPGL的家族史，使其显得零星。 10例患者中有9名患者表现出异常的PPGL特异性生化标志物，主要是甲肾上腺素能和/或多巴胺能表型，这表明它们在诊断和监测疾病方面的效用。 68Ga-核PET在这些肿瘤的定位中优于其他成像方式。除手术外，接受常规疗法的7例患者中，所有7名接受常规疗法（化学疗法，生长抑素模拟疗法，放射治疗，131i-MIBG，肽受体放射性核素疗法）的所有患者都显示出进展。 pPGL的成像方面 可用于诊断，分期和随访的多种放射性核素成像技术。除了检测和定位疾病的能力之外，这些成像方法在细胞和分子水平上的这些肿瘤可以多样化，并可以指导治疗。我们更新了由EANM和SNMMI共同批准的指南，不仅可以协助核医学从业人员的选择和性能，不仅可以选择和性能，而且还提供了当前可用的单光子发射计算机断层扫描和正电子发射断层扫描程序，还可以解释和报告PPGL患者的结果。我们还发表了有关基因组表征时代PPGL分子成像和放射性核素治疗的评论。 PPGL的代谢方面 棕色脂肪组织（BAT）激活是通过去甲肾上腺素对肾上腺素受体（-ars）的作用来介导的。在某些恶性肿瘤中，BAT激活与较高的癌症活性有关。一项回顾性病例对照研究，其中包括342例PPGL患者，他们在美国国家卫生研究院（NIH）接受了18F-FLUORO-2-葡萄糖-D-葡萄糖正电子发射断层扫描（18F-FDG PET/CT）成像。与对照组相比，在18F-FDG PET/CT上存在活性BAT与总体存活率降低有关。调整SDHB突变后，该关联仍然很重要。 BAT组中的中位血浆去甲肾上腺素高于对照组。两组的PPGL中，较高的血浆去甲肾上腺素水平与死亡率之间存在显着关联。 PPGL的治疗方面： PPGL通常是良性神经内分泌肿瘤。但是，琥珀酸脱氢酶B亚基（SDHB）中具有突变的PPGL的预后不良，并且经常出现转移性病变。 SDHB突变的PPGL在氧代谢途径中表现出失调，包括假氧气和活性氧的形成，这表明靶向氧化还原平衡途径可能是一种潜在的治疗方法。通过研究较低的SDHB水平的PPGLS细胞，我们表明伪粘氧化导致铁转运蛋白的表达升高，包括转铁蛋白（TF），转铁蛋白受体2（TFR2）和二价金属转运蛋白1（SLC11A2； DMT1），导致铁的积累。这种铁超负荷导致氧化应激升高。药理学浓度下的抗坏血酸（维生素C）破坏了氧化还原稳态，诱导了SDHB水平低的PPGL细胞中DNA氧化损伤和细胞凋亡。此外，通过带有PPGL同种异体移植的临床前动物模型，我们证明了药物抗坏血酸抑制了SDHB-LOW转移性病变并延长了总体存活率。这里的数据表明，用药理学抗坏血酸将氧化还原稳态作为癌症脆弱性是SDHB突破性PPGL的有前途的治疗策略。 从机械上讲，核因子2与2相关因子2（NRF2）引导的谷胱甘肽从头合成在支持细胞存活和SDHB敲低细胞的增殖方面起着关键作用，我们发现NRF2阻断了SDHB-DECYNIDENIDERITION在SDHB-DECEFIF-DEFIF-DEFIF-DECENIDENIDE中的促进性氧化不仅会促进SDHB-DECENIDENIDERID，但DECTEN nrf2 nrf2 nrf2 nrf2 nrf2 nrf2 nrf2 nrf2 nrf2 nrf2 bose nrf2。 损害。 Brusatol是一种有效的NRF2抑制剂，在抑制SDHB基因抑制体内的转移性病变方面具有有希望的作用，在带有PPGL同种异体移植物的小鼠中，总体存活率延长。我们的发现凸显了针对NRF2驱动的谷胱甘肽代谢途径对SDHB突变的PPGL的新型治疗策略。 作为欧洲高血压学会内分泌高血压工作组的成员，我们概述了基于当前在PPGL流行病学，遗传学，诊断，治疗中的PPGL知识的PPGLS患者评估和治疗PPGL的方法的最新方法