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

该科正在以患者为中心开展有关嗜铬细胞瘤和副神经节瘤（PPGL）的病因学、流行病学、病理生理学、遗传学、诊断和治疗的研究。项目不仅包括转化研究——将基础科学知识应用于临床诊断、病理生理学和治疗——还包括逆向转化研究，其中对临床发现的理解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，该科的战略基于 NIH 研究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工作台级组件连接在一起。以患者为导向的部分（医学神经内分泌学）目前是我们的假设和发现的主要驱动力。两个实验室级组成部分（肿瘤发病机制、遗传学、化学和生物标志物以及实验免疫疗法）首先强调为途径和靶标发现量身定制的基础研究技术，其次强调将发现发展到临床应用。 PPGL 的临床和遗传方面 PPGL 在儿童中很少见，仅有少数 SDHB 突变相关病例。以前对儿童的研究是在小规模队列中进行的。这一大批儿科患者为评估临床结果提供了可靠的数据。 38 名男性和 26 名女性被诊断患有 PPGL，中位年龄为 13 岁。大多数患者表现出去甲肾上腺素分泌过多，73.44%的患者最初表现为孤立性肿瘤。 70% 的患者在中位年龄 16 岁时发生转移，大多数在诊断前 2 年和诊断后 12-18 年被诊断出来。诊断时存在转移对男性的生存有强烈的负面影响，但对女性则不然。估计的5年、10年和20年生存率分别为100%、97.14%和77.71%。本报告强调了治疗具有 SDHB 突变相关 PHEO/PGL 的儿科患者的几个重要方面。 SDHB 突变携带者的初步诊断评估应在 5-6 岁时开始，初步检查重点关注腹部区域。诊断后的前 2 年进行彻底的随访至关重要，并且由于转移风险增加，因此在诊断后 10-20 年需要更频繁的随访。尽管这个年龄组早在诊断后 5 年内就发生了转移，但我们已经表明，总体 20 年预后和生存率良好。 儿茶酚胺分泌会导致与 PPGL 相关的临床后遗症，儿茶酚胺水平升高可导致高血压、快速心律失常、多器官衰竭和死亡。我们介绍过伊伐布雷定是一种市售药物，直接作用于心脏窦房结，用于治疗严重儿茶酚胺引起的快速心律失常。我们还发表了一些关于贲门 PGL 以及心律失常治疗的综合评论。 在另一项研究中，我们评估了具有 SDHA 基因突变的 PPGL 患者。我们的研究结果表明，这些肿瘤可能发生在肾上腺外的早期位置，表现出攻击性，并且有在短时间内发展为转移性疾病的倾向。我们的患者都没有 PPGL 家族史，这使得他们看起来是散发性的。十分之九的患者表现出异常的 PPGL 特异性生化标志物，主要是去甲肾上腺素能和/或多巴胺能表型，表明它们在诊断和监测疾病方面的实用性。 68Ga-DOTATATE PET 在这些肿瘤的定位方面优于其他成像方式。除手术外，接受常规治疗（化疗、生长抑素类似物治疗、放射治疗、131I-MIBG、肽受体放射性核素治疗）的 7 名患者中，所有 7 名均出现进展。 PPGL 的成像方面 多种放射性核素成像技术可用于 PPGL 的诊断、分期和随访。除了检测和定位疾病的能力之外，这些成像方法还可以在细胞和分子水平上不同地表征这些肿瘤，并可以指导治疗。我们更新了 EANM 和 SNMMI 联合批准的指南，不仅帮助核医学从业者选择和执行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，还帮助解释和报告 PPGL 患者的结果。我们还发表了基因组表征时代PPGL分子影像和放射性核素治疗的综述。 PPGL 的代谢方面 棕色脂肪组织 (BAT) 的激活是通过去甲肾上腺素对 β 肾上腺素受体 (-AR) 的作用介导的。在某些恶性肿瘤中，BAT 激活与较高的癌症活性相关。一项回顾性病例对照研究，纳入了 342 名在美国国立卫生研究院 (NIH) 接受 18F-氟-2-脱氧-D-葡萄糖正电子发射断层扫描-计算机断层扫描 (18F-FDG PET/CT) 成像的 PPGL 患者。与对照组相比，18F-FDG PET/CT 上存在活性 BAT 与总生存率降低相关。在调整 SDHB 突变后，这种关联仍然显着。 BAT组的血浆去甲肾上腺素中位数高于对照组。两组中较高的血浆去甲肾上腺素水平与 PPGL 死亡率之间存在显着相关性。 PPGL 的治疗方面： PPGL 通常是良性神经内分泌肿瘤。然而，琥珀酸脱氢酶 B 亚基 (SDHB) 突变的 PPGL 预后较差，并且经常发生转移性病变。 SDHB 突变的 PPGL 在氧代谢途径中表现出失调，包括假性缺氧和活性氧的形成，表明针对氧化还原平衡途径可能是一种潜在的治疗方法。通过研究 SDHB 水平低的 PPGL 细胞，我们发现假性缺氧导致铁转运蛋白表达升高，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)，从而导致铁积累。这种铁超载导致氧化应激升高。药理学浓度的抗坏血酸（维生素 C）会破坏氧化还原稳态，在低 SDHB 水平的 PPGL 细胞中诱导 DNA 氧化损伤和细胞凋亡。此外，通过 PPGL 同种异体移植的临床前动物模型，我们证明药理抗坏血酸可抑制 SDHB 低转移性病变并延长总体生存期。这里的数据表明，利用药理抗坏血酸将氧化还原稳态作为癌症脆弱性，是 SDHB 突变 PPGL 的一种有前景的治疗策略。 从机制上讲，核因子红细胞 2 相关因子 2 (NRF2) 引导的谷胱甘肽从头合成在支持 SDHB 敲低细胞的细胞存活和增殖中发挥着关键作用。 损害。 Brusatol 是一种有效的 NRF2 抑制剂，在抑制 SDHB 基因抑制的体内转移性病变方面显示出良好的效果，并延长了 PPGL 同种异体移植小鼠的总生存期。我们的研究结果强调了一种针对 NRF2 驱动的谷胱甘肽代谢途径来对抗 SDHB 突变 PPGL 的新治疗策略。 作为欧洲高血压学会内分泌高血压工作组的成员，我们根据 PPGL 流行病学、遗传学、诊断、治疗的现有知识概述了评估和治疗 PPGL 患者的最新方法。