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Diagnosis, Localization, Pathophysiology, and Molecular Biology of Pheochromocytoma and Paraganglioma

• Karel Pacak, MD, PhD, DSc, Head, Section on Medical Neuroendocrinology
• Sara Talvacchio, BSN, Research Nurse
• Alberta Derkyi, CRNP, Nurse Practitioner
• Josephine Ezemobi, CRNP, Nurse Practitioner
• Tamara Prodanov, MD, Clinical Trial Database (CTDB) Coordinator
• Thanh-Truc Huynh, MS, Biologist
• Matthew Arman Nazari, MD, Visiting Fellow
• Suman Goshal, PhD, Postdoctoral Visiting Fellow
• Katerina Hadrava Vanova, PhD, Postdoctoral Visiting Fellow
• Abishek Jha, MBBS, Postdoctoral Visiting Fellow
• Ondrej Uher, MSc, Predoctoral Visiting Fellow
• Kailah Charles, BS, Predoctoral Fellow
• Mayank Patel, MD, Volunteer

Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare but clinically important chromaffin-cell tumors that typically arise, respectively, from the adrenal gland and from extra-adrenal paraganglia. The clinical features and consequences of PHEO/PGL, collectively known as PPGLs, result from the overproduction and release of catecholamines (norepinephrine and epinephrine). An undetected PHEO/PGL poses a hazard to patients undergoing surgery, childbirth, or general anesthesia because of the potential for excess catecholamine secretion, which can result in significant, often catastrophic outcomes. Diagnosing and localizing a PHEO/PGL can be challenging. Plasma and urinary catecholamines, as well as their metabolites, and radio-iodinated metaiodobenzylguanidine (MIBG) scanning can yield false-positive or false-negative results in patients harboring the tumor, and computed tomography (CT) and magnetic resonance imaging (MRI) lack sufficient specificity. The molecular mechanisms by which genotypic changes predispose to the development of PHEO/PGL remain unknown, even in patients with identified mutations. Moreover, in patients with hereditary predispositions, PPGLs differ in terms of their growth, malignant potential, catecholamine phenotype, responses to standard screening tests, various imaging modalities, and therefore to different therapeutic options. We focus on developmental, molecular, genetic, epigenetic, proteomic, metabolomic, immunologic, and other types of studies to investigate the bases for a predisposition to develop PPGLs and the expression of various neurochemical phenotypes and malignant potentials, including therapeutic responses and appropriate follow-up.

Clinical and genetic aspects of pheochromocytoma and paraganglioma

We used single-nuclei RNA-Seq and bulk-tissue gene-expression data to characterize the cellular composition of pheochromocytomas (PC), paragangliomas (PGs), and normal adrenal tissues, to refine tumor gene-expression subtypes, and to make clinical and genotypic associations. We confirmed seven PCPG gene–expression subtypes with significant genotype and clinical associations. Tumors with mutations in VHL (Von-Hippel-Lindau gene), SDH–encoding genes (SDHx), or MAML3 (mastermind like transcriptional coactivator 3)–fusions were characterized by hypoxia-inducible factor signaling and neoangiogenesis. PCPGs had few infiltrating lymphocytes but abundant macrophages. While neoplastic cells transcriptionally resembled mature chromaffin cells, early chromaffin and neuroblast markers were also features of some PCPG subtypes. The gene-expression profile of metastatic SDHx–related PCPG indicated that these tumors have elevated cellular proliferation and a lower number of non-neoplastic Schwann cell–like cells, while GPR139 (G-protein coupled receptor 139) is a potential theranostic target. Our findings therefore clarified the diverse transcriptional programs and cellular composition of PCPGs and identified biomarkers of potential clinical significance.

Metabolic dysfunction mutations can impair energy sensing and cause cancer. Loss of function of the mitochondrial tricarboxylic acid (TCA) cycle enzyme subunit succinate dehydrogenase B (SDHB) results in various forms of cancer typified by PC. We delineated a signaling cascade in which the loss of SDHB induces the Warburg effect, triggers dysregulation of [Ca²⁺]_i, and aberrantly activates calpain and protein kinase Cdk5, through conversion of its cofactor from p35 to p25. Consequently, aberrant Cdk5 initiates a phospho-signaling cascade in which GSK3 inhibition inactivates energy sensing by AMP kinase through dephosphorylation of the AMP kinase γ subunit PRKAG2. Overexpression of p25-GFP in mouse adrenal chromaffin cells also elicits this phosphorylation signaling and causes PC. A potent Cdk5 inhibitor, MRT3-007, reversed this phospho-cascade, invoking a senescence-like phenotype. This therapeutic approach halted tumor progression in vivo. Thus, we revealed an important mechanistic feature of metabolic sensing and demonstrated that its dysregulation underlies tumor progression in PC and likely other cancers.

Another retrospective study included 582 patients with PCPGs and 57 with HNGPLs (Head and neck paragangliomas). Disease-specific survival (DSS) was assessed according to age, location and size of tumors, recurrent/metastatic disease, genetics, plasma metanephrines, and methoxytyramine. Among all patients with PCPGs, multivariable analysis indicated that, apart from older age and presence of metastases, shorter DSS was also significantly associated with extra-adrenal tumor location and higher plasma methoxytyramine and normetanephrine. Among patients with HNPGLs, those with metastases presented with significantly longer DSS than patients with metastatic PCPGs, and only plasma methoxytyramine was an independent predictor of DSS. For patients with metastatic PCPGs, multivariable analysis revealed that, apart from older age, shorter DSS was significantly associated with the presence of synchronous metastases and higher plasma methoxytyramine burden. We concluded that DSS among patients with PCPGs/HNPGs relates to several presentations of the disease that may provide prognostic markers. In particular, the independent associations of higher methoxytyramine with shorter DSS in patients with HNPGLs and metastatic PCPGs suggest the utility of this biomarker to guide individualized management and follow-up strategies in affected patients.

In the hope of discovering new markers for metastatic or aggressive phenotypes of PCPGs, we also analyzed the noncoding transcriptome from patient gene-expression data in The Cancer Genome Atlas. Differential expression of miRNAs was observed between PCPG molecular subtypes. We specifically characterized candidate miRNAs that are upregulated in pseudohypoxic PCPGs with mutations in SDHB and/or SDHD (succinate dehydrogenase complex subunit D), which are mutations associated with unfavorable clinical outcomes. Our computational analysis identified four candidate miRNAs that showed higher expression in metastatic than in non-metastatic PCPGs: miR-182, miR-183, miR-96, and miR-383. We also found six candidate lncRNAs harboring opposite expression patterns from the miRNAs when we analyzed the expression profiles of their predicted target lncRNAs. Three of these lncRNA candidates, USP3-AS1, LINC00877, and AC009312.1, were found to have lower expression in metastatic than in non-metastatic PCPGs. Using univariate and multivariate analysis, we found miRNA miR-182 to be an independent predictor of metastasis-free survival in PCPGs. In summary, we identified candidate miRNA and lncRNAs associated with metastasis-free survival in PCPGs.

Imaging of pheochromocytomas and paragangliomas

The first study identified the importance of positron emission tomographic (PET) and anatomic imaging modalities and their individual performances in detecting succinate dehydrogenase A (SDHA)–related metastatic PCPGs. The detection rates of PET modalities ⁶⁸Ga-DOTATATE, ¹⁸F-FDG, and ¹⁸F-FDOPA, along with the combination of computed tomography (CT) and magnetic resonance imaging (MRI), were compared in a cohort of 11 patients with metastatic PCPGs in the setting of a germline SDHA mutation. We evaluated the imaging detection performances at three levels: overall lesions, anatomic regions, and on a patient-by-patient basis. ⁶⁸Ga-DOTATATE PET demonstrated an average lesion-based detection rate of 88.6%, while ¹⁸F-FDG, ¹⁸F-FDOPA, and CT/MRI showed detection rates of 82.9%, 39.8%, and 58.2%, respectively. The study found that ⁶⁸Ga-DOTATATE best detects lesions in a subset of patients with SDHA–related metastatic PCPGs. However, ¹⁸F-FDG did detect more lesions in the liver, mediastinum, and abdomen/pelvis anatomic regions, showing the importance of a combined approach using both these PET modalities in evaluating SDHA–related PCPGs.

Recent professional society guidelines for radionuclide imaging of sporadic PC recommend ¹⁸F-fluorodihydroxyphenylalanine (¹⁸F-FDOPA) as the radiotracer of choice, deeming ⁶⁸Ga-DOTATATE and FDG to be second- and third-line agents, respectively. An additional agent, ¹⁸F-fluorodopamine (¹⁸F-FDA), remains experimental for PC detection. A paucity of research has performed head-to-head comparison among these agents. Thus, the purpose of the second study was to perform an intra-individual comparison of ⁶⁸Ga-DOTATATE PET/CT, FDG PET/CT, ¹⁸F-FDOPA PET/CT, ¹⁸F-FDA PET/CT, CT, and MRI in visualization of sporadic primary PC. This prospective study enrolled patients referred with clinical suspicion for sporadic PC. Patients were scheduled for ⁶⁸Ga-DOTATATE PET/CT, FDG PET/CT, ¹⁸F-FDOPA PET/CT, ¹⁸F-FDA PET/CT, whole-body staging CT (portal venous phase), and MRI within a three-month period. PET/CT examinations were reviewed by two nuclear medicine physicians, and CT and MRI were reviewed by two radiologists; differences were resolved by consensus. Readers scored lesions in terms of confidence in diagnosis of PC (1-5 scale; 4-5 considered positive for PC). Lesion-to-liver SUV_max (maximum standardized uptake value) was computed using both readers' measurements. Inter-reader agreement was assessed using intra-class correlation coefficients (ICCs) for SUV_max. Analysis included only patients with histologically confirmed PC on resection, i.e., 14 patients (eight women, six men; mean age, 52.4 ± 16.8 years). Both ⁶⁸Ga-DOTATATE PET/CT and FDG PET/CT were completed in all 14 patients, ¹⁸F-FDOPA PET/CT in 11, ¹⁸F-FDA PET/CT in 7, CT in 12, and MRI in 12. Given that ¹⁸F-FDOPA PET/CT yielded the maximum positivity rate, the findings from this small intraindividual comparative study support ¹⁸F-FDOPA PET/CT as a preferred first-line imaging modality in evaluation of sporadic PC.

Immune, proteomic, and metabolic aspects of pheochromocytoma and paraganglioma

PCPGs are rare neuroendocrine tumors derived from neural crest cells. Germline variants in approximately 20 PCPGs susceptibility genes are found in about 40% of patients, half of which are found in the genes that encode SDH. Patients with SDHB–mutated PCPGs exhibit a higher likelihood of developing metastatic disease, which can be partially explained by the metabolic cell reprogramming and redox imbalance caused by the mutation. Reactive oxygen species (ROS) are highly reactive molecules involved in a many important signaling pathways. A moderate level of ROS production can help regulate cellular physiology; however, an excessive level of oxidative stress can lead to tumorigenic processes, including stimulation of growth factor–dependent pathways and the induction of genetic instability. Tumor cells effectively exploit antioxidant enzymes in order to protect themselves against harmful intracellular ROS accumulation, which highlights the essential balance between ROS production and scavenging. Exploiting ROS accumulation can be used as a possible therapeutic strategy in ROS–scavenging tumor cells. We focused on the role of ROS production in PCPGs, predominantly in SDHB–mutated cases, and on potential strategies and approaches to anticancer therapies by enhancing ROS production in these difficult-to-treat tumors.

To identify new therapeutic targets, we performed a detailed membrane-focused proteomic analysis of five human PG samples. Using the Pitchfork strategy, which combines specific enrichments of glycopeptides, hydrophobic transmembrane segments, and non-glycosylated extra-membrane peptides, we identified over 1,800 integral membrane proteins (IMPs). We found 45 “tumor enriched” proteins, i.e., proteins identified in all five PGs but not found in control chromaffin tissue. Among them, 18 IMPs were predicted to be localized on the cell surface, a preferred drug targeting site, including prostate-specific membrane antigen (PSMA), a well established target for nuclear imaging and therapy of advanced prostate cancer. Using specific antibodies, we verified PSMA expression in 22 well characterized human PCPG samples. Compared with control chromaffin tissue, PSMA was markedly overexpressed in high-risk PCPGs belonging to the established Cluster 1, which is characterized by worse clinical outcomes, pseudohypoxia, multiplicity, recurrence, and metastasis, specifically including SDHB, VHL, and EPAS1 mutations. Using immunohistochemistry, we localized PSMA expression to tumor vasculature. Our study provides the first direct evidence of PSMA over-expression in PPGLs, which could translate to therapeutic and diagnostic applications of anti–PSMA radio-conjugates in high-risk PCPGs.

Immunotherapy has become an essential part of cancer treatment. Discovery of tumor-specific epitopes through tumor sequencing has revolutionized patient outcomes in many types of cancers that were previously untreatable. However, the majority of solid metastatic cancers, such as PHEO, are resistant to this approach. Therefore, understanding immune cell composition in primary and distant metastatic tumors is important for therapeutic intervention and diagnostics. Combined mannan-BAM (biocompatible anchor for cell membrane), TLR ligand (Toll-like receptor), and anti–CD40 (CH40 is a costimulatory protein found on antigen-presenting cells) antibody-based intra-tumoral immunotherapy (MBTA therapy) previously resulted in the complete eradication of murine subcutaneous PHEO and demonstrated a systemic antitumor immune response in a metastatic model. We further evaluated this systemic effect using a bilateral PHEO model, performing MBTA therapy through injection into the primary tumor and using distant (non-injected) tumors to monitor size changes and detailed immune cell infiltration. MBTA therapy suppressed the growth not only of injected but also of distal tumors and prolonged the survival of MBTA–treated mice. Our flow-cytometry analysis showed that MBTA therapy led to increased recruitment of innate and adaptive immune cells in both tumors and the spleen. Moreover, adoptive CD4⁺ T cell transfer from successfully MBTA–treated mice (i.e., subcutaneous PHEO) demonstrates the importance of such cells in long-term immunological memory. In summary, the study unravels further details on the systemic effect of MBTA therapy and its use for tumor and metastasis reduction or even elimination

We further extended the MBTA therapy to other tumors and applications in close collaboration with NCI investigators. For example, emerging evidence is demonstrating the extent of T cell infiltration within the tumor micro-environment and thus has favorable prognostic and therapeutic implications. Hence, immuno-therapeutic strategies that augment the T cell signature of tumors hold promising therapeutic potential. Recently, immuno-therapy based on intra-tumoral injection of MBTA demonstrated promising potential to modulate the immune phenotype of injected tumors, including PHEO. The strategy promotes the phagocytosis of tumor cells to facilitate the recognition of tumor antigens and induce a tumor-specific adaptive immune response. Using a syngeneic colon carcinoma model, we demonstrated MBTA's potential to augment CD8⁺ T cell tumor infiltrate when administered intra-tumorally or subcutaneously as part of a whole tumor cell vaccine. Both immuno-therapeutic strategies proved effective in controlling tumor growth, prolonged survival, and induced immunological memory against the parental cell line. Collectively, our investigation demonstrates MBTA's potential to trigger a potent anti-tumor immune response.

We also reviewed the most promising glioblastoma vaccination strategies to contextualize the MBTA vaccine. By reviewing current evidence using translational tumor models supporting MBTA vaccination, we evaluated the underlying principles that validate its clinical applicability. We also showed the translational potential of MBTA vaccination as a possible immunotherapy in glioblastoma, along with established surgical and immunologic cancer treatment paradigms.

Therapeutic aspects of pheochromocytoma and paraganglioma

Aggressive PCPGs are difficult to treat, and molecular targeting is being increasingly considered, but with variable results. We investigated established and novel molecular-targeted drugs and chemotherapeutic agents for the treatment of PCPGs in human primary cultures and murine cell line spheroids. In PCPGs from 33 patients, including seven metastatic PCPGs, we identified germline or somatic driver mutations in 79% of cases, allowing us to assess potential differences in drug responsivity between pseudohypoxia-associated cluster 1-related (n = 10) and kinase signaling–associated cluster 2–related (n = 14) PCPG primary cultures. Single anti-cancer drugs were either more effective in cluster 1 (cabozantinib, selpercatinib, and 5-FU) or similarly effective in both clusters (everolimus, sunitinib, alpelisib, trametinib, niraparib, entinostat, gemcitabine, AR-A014418, and high-dose zoledronic acid). High-dose estrogen and low-dose zoledronic acid were the only single substances more effective in cluster 2. Neither cluster 1– nor cluster 2–related patient primary cultures responded to temozolomide, dabrafenib, octreotide, or HIF-2a inhibitors. We showed particular efficacy of targeted combination treatments (cabozantinib/everolimus, alpelisib/everolimus, alpelisib/trametinib) in both clusters, with higher efficacy of some targeted combinations in cluster 2 and overall synergistic effects (cabozantinib/everolimus, alpelisib/trametinib) or synergistic effects in cluster 2 (alpelisib/everolimus). Cabozantinib/everolimus combination therapy, gemcitabine, and high-dose zoledronic acid appear to be promising treatment options with particularly high efficacy in SDHB–mutant and metastatic tumors. In conclusion, only minor differences regarding drug responsivity were found between cluster 1 and cluster 2: some single anti-cancer drugs were more effective in cluster 1 and some targeted combination treatments were more effective in cluster 2.

SDH tumors, including PCPGs, hereditary leiomyomatosis and renal cell cancer–associated renal cell carcinoma (HLRCC–RCC), and gastrointestinal stromal tumors (GISTs) without KIT or platelet-derived growth factor receptor alpha mutations are often resistant to cytotoxic chemotherapy, radiotherapy, and many targeted therapies. We evaluated guadecitabine, a dinucleotide containing the DNA methyltransferase inhibitor decitabine, in these patient populations. Phase II study of guadecitabine (subcutaneously, 45mg/m2/day for five consecutive days, planned 28–day cycle) assessed clinical activity (according to Response Evaluation Criteria in Solid Tumors v.1.1) across three strata of patients with dSDH GIST, PCPG, or HLRCC-RCC. A Simon optimal two-stage design (target response rate 30% rule out 5%) was used. Biologic correlates (methylation and metabolites) from peripheral blood mononuclear cells (PBMCs), serum, and urine were analyzed. Nine patients (seven with dSDH GIST, one each with PGL and HLRCC-RCC, six females and three males, age range 18–57 years-old) were enrolled. Two patients developed treatment-limiting neutropenia. No partial or complete responses were observed (range 1–17 cycles of therapy). Biologic activity assessed as global demethylation in PBMCs was observed. No clear changes in metabolite concentrations were observed. We concluded that guadecitabine was tolerated in patients with SDH tumors with manageable toxicity. While 4/9 patients had prolonged stable disease there were no objective responses. Thus, guadecitabine did not meet the target of 30% response rate across SDH tumors at this dose, though signs of biologic activity were noted.

Animal model of pheochromocytoma and cell culture studies

We previously identified the syndrome of multiple paragangliomas and pheochromocytomas, duodenal somatostatinoma, and polycythemia resulting from post-zygotic EPAS1 (HIF2A)-gain-of-function mutations (also called Pacak-Zhuang syndrome). The mutations, located in the oxygen-degradation domain (ODD) of hypoxia-inducible factor-2alpha (HIF-2alpha), have been shown to impair hydroxylation by prolyl hydroxylase domain–containing protein 2 (PHD2) and subsequent association with the von Hippel-Lindau (VHL) protein. In that situation, degradation of HIF-2alpha is impaired, resulting in its stabilization, prolonged activation, lack of response to normal or increasing oxygen tension, and activation of the transcription of many genes participating in tumorigenesis. Recently, in collaboration with NCI investigators, we developed transgenic mice with a gain-of-function Epas1^A529V mutation (corresponding to human EPAS1^A530V), which demonstrated elevated levels of erythropoietin and polycythemia, a reduced urinary metanephrine-to-normetanephrine ratio, and increased expression of somatostatin in the ampullary region of the duodenum. The findings demonstrate the vital roles of EPAS1 mutations in development of the syndrome and the great potential of the Epas1^A529V animal model for further pathogenesis and therapeutics studies. The model is also being used to study other malformations in animals as well as to match them with those seen in our patients (neurological, vascular, and ocular malformations) as described below.

Patients referred to the NIH for new, recurrent, and/or metastatic PHEO/PGL were confirmed for the EPAS1 gain-of-function mutation; imaging was conducted for vascular malformations. We evaluated the Epas1^A529V transgenic syndrome mouse model, corresponding to the mutation initially detected in the patients (EPAS1^A530V), for vascular malformations by intravital 2-photon microscopy of meningeal vessels, terminal vascular perfusion with Microfil silicate polymer and subsequent intact ex vivo 14T MRI and micro–CT, and histologic sectioning and staining of the brain and identified pathologies. Further, we evaluated retinas from corresponding developmental time points (P7, P14, and P21) and the adult dura by immunofluorescent labeling of vessels and confocal imaging. We identified a spectrum of vascular malformations in all nine syndromic patients and in all our tested mutant mice. Patient vessels had higher variant allele frequency than adjacent normal tissue. Veins of the murine retina and intracranial dura failed to regress normally at the expected developmental time points. The findings add vascular malformation as a new clinical feature of the EPAS1 gain-of-function syndrome.

Publications

1. Zethoven M, Martelotto L, Pattison A, Bowen B, Balachander S, Flynn A, Rossello FJ, Hogg A, Miller JA, Frysak Z, Grimmond S, Fishbein L, Tischler AS, Gill AJ, Hicks RJ, Dahia PLM, Clifton-Bligh R, Pacak K, Tothill RW. Single-nuclei and bulk-tissue gene-expression analysis of pheochromocytoma and paraganglioma links disease subtypes with tumor microenvironment. Nat Commun 2022 13:1–18.
2. Ligon JA, Sundby RT, Wedekind Malone MF, Arnaldez FI, Del Rivero J, Wiener L, Srinivasan R, Spencer M, Carbonell A, Lei H, Shern J, Steinberg SM, Figg WD, Peer CJ, Zimmerman S, Moraly J, Xu X, Fox S, Chan K, Barbato MI, Andresson T, Taylor N, Pacak K, Killian JK, Dombi E, Linehan WM, Miettinen M, Piekarz R, Helman LJ, Meltzer P, Widemann B, Glod J. A phase II trial of guadecitabine in children and adults with SDH-deficient GIST, pheochromocytoma, paraganglioma, and HLRCC-associated renal cell carcinoma. Clin Cancer Res 2023 29(2):341–348.
3. Pamporaki C, Prodanov T, Meuter L, Berends AMA, Bechmann N, Constantinescu G, Beuschlein F, Remde H, Januszewicz A, Kerstens MN, Timmers HJLM, Taïeb D, Robledo M, Lenders JWM, Pacak K, Eisenhofer G. Determinants of disease-specific survival in patients with and without metastatic pheochromocytoma and paraganglioma. Eur J Cancer 2022 169:32–41.
4. Jha A, Patel M, Carrasquillo JA, Ling A, Millo C, Saboury B, Chen CC, Wakim P, Gonzales MK, Meuter L, Knue M, Talvacchio S, Herscovitch P, Rivero JD, Chen AP, Nilubol N, Taïeb D, Lin FI, Civelek AC, Pacak K. Sporadic primary pheochromocytoma: a prospective intraindividual comparison of six imaging tests (CT, MRI, and PET/CT using 68Ga-DOTATATE, FDG, 18F-FDOPA, and 18F-FDA). Am J Roentgenol 2022 218:342–350.
5. Nölting S, Bechmann N, Taieb D, Beuschlein F, Fassnacht M, Kroiss M, Eisenhofer G, Grossman A, Pacak K. Personalized management of pheochromocytoma and paraganglioma. Endocr Rev 2022 43:199–239.

Collaborators

• James Bibb, PhD, University of Alabama Comprehensive Cancer Center, University of Alabama at Birmingham Medical Center, Birmingham, AL
• Clara C. Chen, MD, Nuclear Medicine Department, Clinical Center, NIH, Bethesda, MD
• Jaydira Del Rivero, MD, Pediatric Oncology Branch, NCI, Bethesda, MD
• Graeme Eisenhofer, PhD, Universität Dresden, Dresden, Germany
• Hans Ghayee, DO, Department of Internal Medicine, University of Florida, Gainesville, FL
• Peter Herscovitch, MD, PET Department, Clinical Center, NIH, Bethesda, MD
• Frank I. Lin, MD, Molecular Imaging Program, NCI, Bethesda, MD
• W. Marston Linehan, MD, Urologic Oncology Branch, NCI, Bethesda, MD
• Corina Millo, MD, PET Department, Clinical Center, NIH, Bethesda, MD
• Jirí Neužil, PhD, Institute of Biotechnology, Czech Academy of Sciences, Prague, Czech Republic
• Seyedehmoozhan Nikpanah, MD, Nuclear Medicine Department, Clinical Center, NIH, Bethesda, MD
• Naris Nilubol, MD, FACS, Surgical Oncology Program, NCI, Bethesda, MD
• Ondrej Petrak, MD, PhD, Third Department of Medicine, General University Hospital, Prague, Czech Republic
• Margarita Raygada, PhD, Section on Endocrinology and Genetics, NICHD, Bethesda, MD
• Mercedes Robledo, PhD, Human Cancer Genetics Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain
• Jared Rosenblum, MD, Neuro-Oncology Branch, NCI, Bethesda, MD
• Douglas Rosing, MD, Translational Medicine Branch, NHLBI, Bethesda, MD
• Kelly Roszko, MD, PhD, Skeletal Disorders and Mineral Homeostasis Section, NIDCR, Bethesda, MD
• Babak Saboury, MD, Nuclear Medicine Department, CC, NIH, Bethesda, MD
• Arthur S. Tischler, MD, PhD, New England Medical Center, Boston, MA
• Richard Tothill, PhD, University of Melbourne Centre for Cancer Research, Melbourne, Australia
• Brad Wood, MD, PhD, Radiology Department, Clinical Center, NIH, Bethesda, MD
• Chunzhang Yang, PhD, Neuro-Oncology Branch, NCI, Bethesda, MD
• Deena Zeltser, MD, Office of the Clinical Director, NICHD, Bethesda, MD
• Zhengping Zhuang, MD, PhD, Neuro-Oncology Branch, NCI, Bethesda, MD

Contact

For more information, email karel@mail.nih.gov or visit https://irp.nih.gov/pi/karel-pacak.

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