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: 9339254
• 负责人: Karel Pacak
• 金额: $ 113.22万
• 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/9339254
• 关键词: Admixture; Basic Science; Biological Markers; Cataloging; Catalogs; Chemistry; Clinical; Clinical Trials; Collaborations; Communities; Confidence Intervals; DNA Methylation; Data; Detection; Development; Diagnosis; Disease; Etiology; Evaluation; Functional Imaging; Functional disorder; Funding; Future; Gene Fusion; Gene Mutation; Genetic Markers; Germ-Line Mutation; Goals; HRAS gene; Head and neck structure; Hypoxia; Image; Inherited; Institutes; Interdisciplinary Study; Isotretinoin; Journals; Knowledge; Laboratories; Lead; Link; Lobbying; MAP Kinase Gene; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant Pheochromocytoma; Medical; Medical center; Metastatic Pheochromocytoma; Methods; MicroRNAs; Molecular; Molecular Biology; Molecular Profiling; Mutation; NF-kappa B; NF1 mutation; Neoplasm Metastasis; Neuroendocrinology; Paraganglioma; Pathogenesis; Pathway interactions; Patients; Pheochromocytoma; Phosphotransferases; Positron-Emission Tomography; Primary Neoplasm; Process; Reporting; Research Personnel; Resources; Secondary Polycythemia; Signal Transduction; Somatic Mutation; Somatostatinoma; Syndrome; Technology; Testing; The Cancer Genome Atlas; Tissues; Topoisomerase-I Inhibitor; Translational Research; United States National Institutes of Health; analog; bHLH-PAS factor HLF; base; clinical Diagnosis; clinical application; driving force; exome sequencing; fluorodeoxyglucose positron emission tomography; fusion gene; gain of function mutation; genetic disorder diagnosis; genome analysis; hemangioblastoma; imaging modality; improved; inhibitor/antagonist; interest; molecular marker; molecular subtypes; patient oriented; patient oriented research; small molecular inhibitor; transcriptome sequencing; triptolide; tumor; tumorigenesis

The Section is conducting patient-oriented research about the etiology, pathophysiology, genetics, diagnosis, and treatment of pheochromocytoma (PHEO) and paraganglioma (PGL). 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. 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 and Chemistry & Biomarkers) emphasize first, technologies of basic research tailored for pathway and target discovery and second, the development of the discoveries into clinical applications. Hereditary PHEO/PGL Previously, we reported a new syndrome, characterized by tumor-specific gain-of-function mutations in hypoxia-inducible factor 2 (HIF2A), leading to the development of multiple PGLs and duodenal somatostatinomas associated with secondary polycythemia (Pacak-Zhuang syndrome). In another study we tested whether duodenal GPGLs share a similar pathogenic mechanism with PGLs associated with somatic HIF2A mutations. Ten GPGL tissues were screened for somatic HIF2A mutation and 2 of them were found to have HIF2A mutation. Similar to this study, we found that some CNS hemangioblastomas were found to have HIF2A mutation. The Cancer Genome Atlas (TCGA) is a comprehensive and coordinated effort to accelerate our understanding of the molecular basis of selected cancers through the application of large-scale genome analysis technologies. TCGA was funded by NCI/NIH, and we lobbied for PHEO and PGL to be included in the TCGA effort. After acceptance, we served as the major collaborative center with Dr. Pacak as co-chair. Together with other investigators, we achieved the largest and most detailed molecular catalogue of PHEOs/PGLs, which included 178 cases analyzed with whole-exome sequencing, copy-number analysis, messenger RNA sequencing, microRNA sequencing, and DNA-methylation analysis. We identified two previously unrecognized molecular alterations including the somatic MAML3 fusion gene and somatic CSDE1 gene mutations that were associated with clinically aggressive disease. Additional molecular discriminants of clinically aggressive disease included ATRX, and SETD2 mutations. We also identified 4 molecular subtypes of PHEO/PGL with distinct molecular alterations and clinical profiles: the kinase signaling subtype (HRAS, RET, and NF1 mutations), (pseudo)hypoxic subtype (SDHB, VHL, and HIF2A mutations), Wnt-altered subtype (CSDE1 mutations and MAML3 fusions), and cortical admixture subtype (MAX mutations). Sixty-nine percent of tumors had driver alterations, which were either germline or somatic mutations or a somatic gene fusion. Driver alterations were essentially mutually exclusive. Patients with clinically aggressive disease had a significantly different molecular profile in their primary tumors as compared to other patients. Although these findings are currently under journal review, the underlying data is already available for any investigator to download and process. Thus, TCGA now offers the PHEO/PGL community an invaluable resource, which may continue to fuel discoveries and ultimately lead to improved understanding of these tumors. Imaging and PHEO/PGL In our first study, 68Ga-DOTATATE PET was prospectively performed in 17 patients with SDHB-related metastatic PHEOs/PGLs45. All patients also underwent 18F-FDG PET and CT/MRI, with 16 of the 17 patients also receiving 18F-fluorodihydroxyphenylalanine (18F-FDOPA) and 18F-FDA PET scans. Detection rates of metastatic lesions were compared among all performed functional imaging studies. 68Ga-DOTATATE PET showed a detection rate of 98.6% 95% confidence interval (CI), 96.5%99.5%, 18F-FDG, 18F-FDOPA, 18F-FDA PET, and CT/MRI showed detection rates of 85.8% (CI, 81.3%89.4%; P < 0.01), 61.4% (CI, 55.6%66.9%; P < 0.01), 51.9% (CI, 46.1%57.7%; P < 0.01), and 84.8% (CI, 80.0%88.5%; P < 0.01), respectively. 68Ga-DOTATATE PET showed a significantly superior detection rate among other functional and anatomical imaging modalities. Thus, we concluded that 68Ga-DOTATATE PET may represent the preferred future imaging modality in the evaluation of SDHB-related metastatic PHEO/PGL. In our subsequent studies we found that 68Ga-DOTATATE PET is also an excellent and superior functional imaging modality to other imaging modalities in the detection of sporadic metastatic PHEO and PGL including those located in the head and neck. These results suggest that treatment using DOTA-analogs, especially 177Lu-DOTATATE can be of a huge interest in patients with metastatic PHEO/PGL. Treatment of PHEO/PGL In several studies we found that topoisomerase I inhibitors (e.g. LMP-400), NF-kappaB inhibitors (e.g. triptolide); MAPK pathway inhibitors (e.g. various statins) with or without 13-cis retinoic acid; a dual mTORC1/2 small molecular inhibitor (AZD 8055); and ATP synthase inhibitors could be potential excellent targets in treatment of metastatic PHEO/PGL. We have initiated collaboration with NCI to use hypomethylating agents in treatment of metastatic PHEO/PGL.

该科正在进行以病人为中心的研究，涉及嗜铬细胞瘤和副神经节瘤的病因、病理生理学、遗传学、诊断和治疗。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，还包括反向转化研究，其中对临床发现的赞赏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，该科的战略是基于NIH研究人员和外部医疗中心之间的多学科合作。我们的部门将一个面向患者的组件与两个台架级组件连接在一起。以病人为导向的组成部分（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。两个实验室水平的组成部分（肿瘤发病机制和化学与生物标志物）强调第一，为途径和靶点发现量身定制的基础研究技术，第二，将发现发展为临床应用。 遗传性PHEO/PGL 以前，我们报道了一种新的综合征，其特征是肿瘤特异性低氧诱导因子2（HIF 2A）的功能获得性突变，导致继发性红细胞增多症相关的多发性PGLs和十二指肠生长抑素瘤（Pacak-Zhuang综合征）的发生。在另一项研究中，我们测试了十二指肠GPGL是否与与体细胞HIF 2A突变相关的PGLs具有相似的致病机制。对10例GPGL组织进行了体细胞HIF 2A突变筛查，发现其中2例存在HIF 2A突变。与本研究相似，我们发现一些中枢神经系统血管母细胞瘤中发现有HIF 2A突变。癌症基因组图谱（TCGA）是一个全面和协调的努力，通过应用大规模基因组分析技术来加速我们对选定癌症分子基础的理解。TCGA由NCI/NIH资助，我们游说PHEO和PGL纳入TCGA工作。接受后，我们担任主要合作中心，帕查克博士担任联合主席。与其他研究人员一起，我们获得了最大和最详细的PHEO/PGLs分子目录，其中包括178例全外显子组测序，拷贝数分析，信使RNA测序，microRNA测序和DNA甲基化分析。我们发现了两个以前未被认识到的分子改变，包括体细胞MAML 3融合基因和体细胞CSDE 1基因突变，与临床侵袭性疾病相关。临床侵袭性疾病的其他分子鉴别因素包括ATRX和SETD 2突变。我们还鉴定了4种具有不同分子改变和临床特征的PHEO/PGL分子亚型：激酶信号传导亚型（HRAS、RET和NF 1突变）、（假）缺氧亚型（SDHB、VHL和HIF 2A突变）、Wnt改变亚型（CSDE 1突变和MAML 3融合）和皮质混合亚型（MAX突变）。69%的肿瘤有驱动基因改变，这些改变要么是种系突变，要么是体细胞突变，要么是体细胞基因融合。驱动程序的更改基本上是相互排斥的。与其他患者相比，具有临床侵袭性疾病的患者在其原发性肿瘤中具有显著不同的分子谱。虽然这些发现目前正在进行期刊审查，但基础数据已经可供任何研究人员下载和处理。因此，TCGA现在为PHEO/PGL社区提供了宝贵的资源，这可能会继续推动发现，并最终导致对这些肿瘤的更好理解。 成像和PHEO/PGL 在我们的第一项研究中，对17例SDHB相关转移性PHEO/PGLs患者前瞻性进行了68 Ga-DOTATATE PET 45。所有患者还接受了18F-FDG PET和CT/MRI，17名患者中有16名还接受了18F-FDOPA和18F-FDA PET扫描。比较所有功能性影像学检查的转移病灶检出率。68 Ga-DOTATATE PET显示检出率为98.6%95%置信区间（CI），96.5%99.5%，18F-FDG、18F-FDOPA、18F-FDA PET和CT/MRI显示检出率为85.8%（CI，81.3%~ 89.4%; P < 0.01）、61.4%（CI，55.6%~ 66.9%; P < 0.01）、51.9%（CI，46.1%~ 57.7%; P < 0.01）和84.8%（CI，80.0%~ 88.5%; P < 0.01）。68 Ga-DOTATATE PET显示出明显优于其他功能和解剖成像模式的上级检出率。因此，我们得出结论，68 Ga-DOTATATE PET可能是未来评价SDHB相关转移性PHEO/PGL的首选成像方式。在我们随后的研究中，我们发现68 Ga-DOTATATE PET在检测散发性转移性PHEO和PGL（包括位于头颈部的转移性PHEO和PGL）方面也是一种优于其他成像方式的上级功能成像方式。这些结果表明，使用DOTA-类似物，特别是177 Lu-DOTATATE的治疗在转移性PHEO/PGL患者中可能具有巨大的意义。 PHEO/PGL的处理 在几项研究中，我们发现拓扑异构酶I抑制剂（如LMP-400）、NF-κ B抑制剂（如雷公藤内酯醇）、MAPK通路抑制剂（如各种他汀类药物）（含或不含13-顺式视黄酸）、双重mTORC 1/2小分子抑制剂（AZD 8055）和ATP合成酶抑制剂可能是治疗转移性PHEO/PGL的潜在优良靶点。我们已经开始与NCI合作，使用低甲基化药物治疗转移性PHEO/PGL。