Lecture outline. Disclosure. Nothing to disclose. Basic and clinical research in pheochromocytoma (PHEO): a winning combination
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1 Basic and clinical research in pheochromocytoma (PHEO): a winning combination Karel Pacak karel@mail.nih.gov Disclosure Nothing to disclose National Institutes of Health Lecture outline The lecture will focus on the main discoveries over the course of the past 4 years.. Summarize current basic-clinical discoveries that represent a winning combination in how we diagnose PHEO patients today: a/ genetics b/ biochemistry c/ metabolomics d/ functional imaging Genetics NF VHL Fränkel Biochemical Diagnosis PHEO/PGL: Continuing progress MEN 2 Colorimetric Assays NF HPLC Assays PHD2 HIF2A PGL syndromes IDH MAX SDHA VHL RET SDHD SDHC SDHB TMEM27 SDHAF2 rule-of-ten defunct 2000 Improved understanding of catecholamine metabolism Shift from catecholamines to metanephrines LC-MS/MS (routine) Methoxytyramine H-RAS FH PHD MDH Promising future therapeutic approaches derived from basic research discoveries Imaging MIBG scintigraphy MRI & CT PET New PET Ligands: 8 F-FDA, 8 F-FDOPA DOTA analogs ( 68 Ga-DOTA-TATE/TOC/NOC) 3. Conclusions/perspectives PGL: paraganglioma PHD: prolyl hydroxylase MDH2: malate dehydrogenase 2 Adapted from G. Eisenhofer
2 Current important facts: PHEO/PGL: Facts In over 50% of PHEOs/PGLs, a genetic defect is known (35-40% have germline and 5-25% harbor somatic mutations); 9 PHEO/PGL susceptibility genes are currently known Biochemical dx. and localization are highly successful There is no satisfactory cure for metastatic PHEO/PGL International studies and consortia are evolving Mitochondrial inner membrane mutations SDHC SDHB 3x[Fe S] Fumarate Mitochondrial matrix Glycolysis SDHD H2 Krebs cycle Hereditary PHEO/PGL Ubiquinol SDHA FADH2 FAD H2 Apoptosis Adapted from Vicha, Taieb, Pacak, Endocrine Relat. Cancer 204; 2:R26 Opocher & Schiavi, Endocr. Pract. 20; Suppl. 3:64 Baysal et al. Science 2000; 287:848 Ubiquinone O 2 O 2 stabilization Angiogenesis Complex III O 2 cycle O 2 ROS ROS ROS Cytochrome C Genomic instability, oncogene activation Lipid, protein, nucleotide synthesis Cell proliferation, cell migration, invasiveness and survival e New genes: A story of metabolic/oxidative stress and hypoxia continues Glucose nucleus ph GLUTs Glucose Hexokinase I II ABL2 EPO = D instability POU5FOCT4 CCND Target mrs DLL4 PDGF VEGF HIF β HIF 2α HIF β Proteomics & metabolomics: The way to new discoveries Lactate Glucose 6 phosphate Phosphoenolpyruvate PKM2 HIF 2α Increased glycolysis Tumorigenesis HRE HRE Upregulation of HIF related genes LDHA Pyruvate HIF /2α PHD HIF2A Acetyl CoA ROS HIF /2α HIF /2α HIF /2α Proteasome degradation Oxalacetate Citrate Isocitrate OH PHDs OH OH H + MDH2 FH H + OXPHOS dysfunction H + Malate Fumarate H + H + α Ketoglutarate Succinyl CoA Glutamate Glutamine Glutamate Gutamate Glutaminolysis VHL FH: fumarate hydratase MDH2: malate dehydrogenase HIF2A: HIF 2 PHD: prolyl hydroxylase Adapted from Vicha, Taieb, Pacak, Endocrine Relat. Cancer 204; 2:R26 Castro-Vega et al. Hum. Mol. Genet. 204; 23: 2440 Ladrue et al. NEJM 2008; 359:2685 Robledo: personal communication; Yang et al. J. Mol. Med.; in press Improve understanding of PHEO/PGL cell biology Improve clinical care for afflicted patients Goodacre et al. Metabolomics, 2005; : 2
3 Methoxytyramine (MTY) as a new biomarker in the diagnosis of PHEO/PGL Cluster Methoxytyramine in cluster & 2 PHEOs/PGLs VHL SDHB SDHD SDHA /C/AF2 NE NE/DA NE/DA NE/DA 7% 72% 67% Low Cluster 2 RET NF TMEM27 MAX We have found that about 70% of SDHB/D PHEOs and 20-30% of head and neck PGLs secrete MTY. EPI/NE EPI/NE EPI/NE NE>EPI Eisenhofer et al. Clin. Chem. 20; 57:4 <5% 8% <5% 0% Adapted from G. Eisenhofer & Fauci et al. Harrison s Principles of Internal Medicine Methoxytyramine (MTY), tumor size, extra-adrenal location, and SDHB as independent predictors of metastatic PHEO/PGL 365 patients with PHEO, including 05 with metastases, 846 subjects without tumors MTY & METASTASIS 4.7-fold higher in patients with than without metastases; independent of tumor burden and NMN levels SIZE & LOCATION Strategy for new genetic screening There is a need for a more cost-effective approach Immunostaining approaches are less expensive than genetic screening SDHB immunohistochemistry detects patients with -related PHEO/PGL SDHB SDHC SDHD 56 tumors included for genotype-specific catecholamine profiles Zelinka et al. Eur.J. Clin. Invest.; 20; 4:2 Eisenhofer et al. Eur. J. Cancer; 202; 48:739 VHL MEN NF- Epinephrine Norepinephrine Dopamine van Nederveen et al. Lancet Oncol. 2009; 0:764 Immunohistochemistry can be used to triage genetic testing; also to detect recently described a SDHA gene mutation in PHEO/PGL Eisenhofer et al. Endocr. Relat. Cancer 20; 8:97 3
4 p< p< p< p<0 p<0 PHEO/PGL & metabolomics () PHEO/PGL & metabolomics (2) 234 PHEOs/PGLs from 233 pts (45 had gene mutations). Training set: 50 tumors; validation set: 84 tumors. Metabolite extraction from fresh-frozen tumors, HPLC-tandem MS used. to fumarate ratio as a predictor for mutations Training set Validation set p<0 p<0 Krebs cycle changes beyond succinate and fumarate :fumarate ratio :fumarate ratio Lactate Pyruvate Glycolysis Acetyl-CoA Malate Oxalo acetate Citrate Lendvai et al. Endocrinology, 204; 55: SDHB/D 2 - SDHB/C/D 2 (n=) (n=39) (n=32) (n=50) High diagnostic performance Table. Diagnostic sensitivity and specificity for succinate:fumarate ratios to identify mutations.0 All PPGLs PPGLs excl. HNP HNP 0.8 Validation set Sensitivity [%] 90.9 (30/33) 00 (5/5) (5/8) Specificity [%] (45/49) (4/44) (4/5) Training and validation set 0.2 Sensitivity [%] 93.2 (4/44) 00 (25/25) 84.2 (6/9) succinate/fumarate, A = 0.94 Specificity [%] (8/87) (77/82) (4/5) - Specificity HNP- head and neck paraganglioma Sensitivity Fumarate Krebs cycle Ketoglutarate Cis-aconitate Isocitrate Richter et al. JCEM, 204; 99:3903 Metabolomics to predict the pathogenicity of unknown mutations MRI HRMAS MAX: Tumor suppressor gene MYC-associated factor X regulates cell proliferation, apoptosis, differentiation; dimerization of MYC-MAX 8 FDOPA mutations of unknown significance Modelling IHC: SDHB PHEO, bilateral; rarely PGL Malignancy in about 0-5% of patients Paternal transmission (similar to SDHD, SDHAF2) Produce NE + EPI Taieb et al; personal communication Camino-Menendez et al. Nat. Genet. 20; 43:663 Burnichon et al. Clin. Cancer Res. 202; 5:2828 4
5 Opposing effects of HIF- and HIF-2 on chromaffin cell phenotypic features: Insights from MYC-associated factor X (MAX) MAX plays an important role in the control of the MYC/MAX pathway and contributes to numerous neoplastic conditions, including neuroblastoma Recently, MAX mutations have been found in some PHEOs/PGLs HIF-2 enhances MYC interaction with MAX to stimulate cancer cell progression; HIF- has the opposite effect in et al. Int. J. Cancer 204; 35:2054 Comino-Mendez et al. Nat. Genet. 20; 43:663 Opposing effects of HIF- and HIF-2 on chromaffin cell phenotypic features: Insights from MYC-associated factor X (MAX) Two PHEO cell lines were used: PC2 (- MAX) and MPC (-HIF2A) Fig. 4 a Pnmt Relative mr expression.2 e PC2w t Silence Hif α PC2 HIF2α Plasmid HIF2α β-actin b Pnmt Relative mr expression PC2w t Silence Hif2 α MPC MPCwt MPC Silence Hifα c Pnmt Relative d PNMT mr expression Activity MPCwt MPC + Hif2α f g Pnmt Relative PNMT mr expression Activity e BrdU FITC-A FITC-A PC2wt 24±0.55% MPCwt 23±0.39% PE-A FITC-A FITC-A D PC2+MAX 6±0.73% MPC+Hif2α 29±0.36% PE-A Fig. 6 PHD Fumarate VHL HIF2α Differentiation blocked Immature phenotype Cluster tumors Cluster Cluster 2 HIF2α HIF2α HIFα Chromaffin progenitors cells HIFα HIFα HIF2α HIFα MYC MAX HIFα HIFα mtor HIF2α TMEM27 Akt Ras NF Differentiation permitted Mature phenotype Cluster 2 tumors RET in et al. Int. J. Cancer 204; 35:2054 The new syndrome of PGL, somatostatinoma and polycythemia The new syndrome of PGL, somatostatinoma and polycythemia Patient Patient 2 URL Patient Patient 2 URL Polycythemia Red cheeks/lips Blue feet 8 yr No < yr Polycythemia Red cheeks/lips Blue feet 8 yr No < yr Erythrocytes Hematocrit Erythropoietin 7, , , Erythrocytes Hematocrit Erythropoietin 7, , , Multiple PGLs Normetanephrine 4 yr 4,834 8 yr Multiple PGLs Normetanephrine 4 yr 4,834 8 yr Multiple SOMs 29 yr No (?) - Multiple SOMs 29 yr No (?) - URL: upper reference limit Zhuang et al. NEJM 202; 367: Zhuang et al. NEJM 202; 367:
6 The new syndrome of PGL, somatostatinoma and polycythemia The new syndrome of PGL, somatostatinoma and polycythemia Patient Patient 2 URL Patient Patient 2 URL Polycythemia Red cheeks/lips Blue feet 8 yr No < yr Polycythemia Red cheeks/lips Blue feet 8 yr No < yr Erythrocytes Hematocrit Erythropoietin 7, , , Erythrocytes Hematocrit Erythropoietin 7, , , Multiple PGLs Normetanephrine 4 yr 4,834 8 yr Multiple PGLs Normetanephrine 4 yr 4,834 8 yr Multiple SOMs 29 yr No (?) - Multiple SOMs 29 yr No (?) - Zhuang et al. NEJM 202; 367: Zhuang et al. NEJM 202; 367: Previous studies related to PHEO/PGL and polycythemia served as a clue to discovering a new syndrome PHEO/PGL & polycythemia Somatic gain-of-function HIF-2 (HIF2A) mutation HIF-2 IHC N: normal adrenal medulla Somatic mutation in HIF2A (PGL) exon 2 (SOM) PHD: prolyl hydroxylase VHL: von Hippel-Lindau protein HIF: hypoxia-inducible factor SDH: succinate dehydrogenase Kaelin Cold Spring Harb. Symp. uant Biol. 20; 76:335 Kaelin Nat. Rev. Cancer 2008; 8:865 Kelin et al. Mol. Cell 2008; 30:393 Ladroue et al. NEJM 2008; 359:2685 Pt.. A530T Pt. 2. A530V 6
7 Other genetic abnormalities in patients with HIF2A mutations A gain of 2p chromosome Hematopoietic cell development Tumor development & progression Comino-Mendez et al. Hum. Mol. Genet. 203; 22:269 Some patients without polycythemia: related to the time at which the mutation occurs? Oncogenic effects of HIF2A mutations in mice Toledo et al. Endocrine Relat. Cancer 203; 20:349 HIF2A mutations: more patients are being discovered Age of onset Mutation Amino Acid Somatic mutation Favier et al., C59T P53S Y Taieb et al C589T A530V Y Comino-Mendez et al., G588A A530T Y 40 C589T A530V Y 3 C59T P53S Y 8 C592T P53L Y 46 C599_604del I533_P534del Y 43 C600_608del P534_D536del Y 78 G65T D539Y Y Toledo et al., C59A P53T Y 47 C59T P53S Y 72 C592T P53L Y? C22A S7Y Y Buffet et al., T586C L529P Y 2 C625T L542P Y/N Toyoda et al., C589A A530E Y Favier et al. NEJM 202; 367:26 Taieb et al. JCEM 203; 98:E908 Comino-Mendez et al. 203; 22:269 Toledo et al. 203; 20:349 Buffet et al. JCEM 204; 99:E369 Toyoda et al. Pediatrics 204; 33:e787 New germline PHD (EGLN2) mutation Some patients with polycythemia and PHEO do not have the HIF2A mutation and they present with normal or slightly elevated EPO levels Germline PHD2 mutations described previously in patients with polycythemia and in one patient also with PGL : A hypermethylator phenotype 45 PHEOs/PGLs were included (7, 2 VHL, 30 NF, 3 RET and 64 others). Immortalized mouse chromaffin cells harboring a complete defect in SDH Increased migration, well inhibited by decitabine (inhibits D methyltransferase activity) Histone methylation was increased (also in human samples) Young et al. J. Mol. Med. in press Letouze et al. Cancer Cell 203; 23: 739 7
8 PHEO and somatostatin receptors: imaging 68 Ga-DOTA analogs: A future imaging approach? PHEOs express 5 somatostatin receptors (SSTRs), allowing for the use of Octreoscan scintigraphy (relatively poor spatial resolution) SSTR imaging can be performed with PET/CT, improving spatial resolution; also provides more rapid and whole-body tomographic imaging for precise anatomic localization [ 68 Ga]-DOTATATE [ 8 F]-FDG [ 8 F]-DOPA [ 8 F]-FDA Available 3 DOTA-coupled peptides include: 68 Ga-DOTATATE, 68 Ga-DOTATOC, 68 Ga-DOTANOC [ 68 Ga]-DOTATATE [ In]-Pentetreotide [ 23 I]-MIBG NIH group & Taieb et al.; ongoing studies Future treatment options: HIF- inhibitors SDHB missense mutations: it is about protein degradation, not production HIF-α translation HIF-α dimerization stabilization HIF-α D binding degradation mr Protein+HDACi mtor & topoisomerase inhibitors Cardiac glycosides PX-478 HSP90 & HDAC inhibitors Acriflavine Antioxidants Amphotericin Anthracyclines HSP90 inhibitors PHD activation protein Semenza et al. Trends Pharmacol. Sci. 202; 8:534 Powers et al. PLoS One 204; 9:e87807 Yang et al. FASEB J. 202; 26:4506 8
9 Other future promising targets for the treatment of metastatic PHEO/PGL Future therapeutic targets. Mitochondrial proton pump modulators 2. SDHB stabilization (HDAC inhibitors) 3. Inhibition of cholesterol synthesis 4. Topoisomerases inhibitors 5. Demethylating agents (5-Azacytidine) Shlomi et al. Plos Comp. Biol. 20; 7: e00208 Lopez-Lazaro Mol. Med. 200; 6:44 Chae et al. Nar. Commun. 203; 4:239 Letouze et al. Cancer Cell 203; 23:739 Nolting et al. Endocrinology 204; 55:2377 Fliedner et al. PLoS One 204; 9:e9772 Baudin et al. Eur. J. Endocrinol. 204; 7:R Powers et al. PLoS One 204; 9:e87807 CONCLUSIONS/PERSPECTIVES Further promote tight collaboration, information exchange, and unique teamwork between patients, clinicians, and scientists across various institutions. Bench-to-bedside and bedside-to-bench projects are most valuable to our success in better treating patients in the near future. Together we have a chance; separately we fail Acknowledgements Many thanks to all the members of my laboratory, attendings, and endocrine, oncology, and surgery fellows for their long hours, dedication, and passion for helping those who suffer. Many thanks to outside NIH co-investigators: G. Eisenhofer, J. Lenders, D. Taieb, S. Fliedner, A. Tischler, H. Timmers, M. Robledo, L. Mercado-Asis, A. Vicha, A. Grossman, H. Ghayee, R. Lechan, Z. Frysak, H. Lehnert, J. Breza, TCGA members, PheoPara Alliance, VHL Alliance and many others AASNT Patients are our passion and we are their hope 9
10 HIF-2 signaling in cluster hereditary PHEO/PGL: Turning the rudder in the right direction? Citrate CS ACO Oxaloacetate MITOCHONDRIA Isocitrate α ketoglutarate IDH OGDH MDH2 L Malate Krebs cycle FH Mitochondrial complex II Fumarate Succinyl CoA SUCLG Δ Cluster HIF-/2 signaling in cluster 2 hereditary PHEO/PGL: Turning the rudder in the right direction? Cluster 2 MAX HIFα mr cmyc HIFα translation (protein synthesis) eif 4E S6K mtorc Raptor TMEM27 HIF β p300 transcriptional activity NUCLEUS HSP90 HRE CPB Rheb Proteasomal degradation CYTOSOL E3 ubiquitinligase complex Cul2 Elongin E2 BElongin C Rbx SSAT2 pvhl U OH OH α ketoglutarate + O 2 HSP90 HSP90 HIF β HRE p300 CBP transcriptional activity PHD Ascorbate + Fe 2+ NUCLEUS NF Ras Growth factors (EGF, TGFα, IGF, NGF, ) TSC/2 Akt PI3K EXTRACELLULAR mtorc2 Receptor tyrosine kinase RET (, IGF R, FGF R, VEGF R, EGF R) HIF promoter NF κb Induction of HIFα expression CYTOSOL The Cancer Genome Atlas Understanding genomics to improve cancer care TCGA facts:. A comprehensive, collaborative effort led by the NIH 2. Announced in 2009 to map the genomes of at least 20 cancers by 204 The glory of medicine is that it is constantly moving forward, that there is always more to learn. 3. Nine rare cancers included PHEO/PGL is one of them (202) 4. Data types: whole exome, mr, and mir sequencing, D methylation, and D copy number Dr. William J. Mayo, Researchers across the US and other nations to collaborate 6. The PHEO/PGL project is expected to be completed by 205 0
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