Malignant Pheochromocytomas and Paragangliomas: Molecular Signaling Pathways and Emerging Therapies

Abstract

Patients having malignant pheochromocytomas and paragangliomas traditionally have been treated with systemic chemotherapy and ¹³¹I-meta-iodobenzylguanidine. However, these therapies have limited efficacy and the potential for significant toxicity. Over the last decade, researchers have discovered new gene mutations associated with malignant pheochromocytomas and paragangliomas, facilitating a better understanding of the molecular pathways involved in the development of these tumors. This new knowledge has brought with it the potential to test new medications that specifically target the signal transduction abnormalities known to be involved in malignant transformation. We are among the groups to have recently reported the use of the tyrosine kinase inhibitor sunitinib in a limited number of patients with malignant pheochromocytomas and paragangliomas. The use of sunitinib was associated with a reduction in the size of the tumors, their biochemical markers, and symptomatic improvement. In this review, we will explore these newly understood molecular pathways and the emerging therapies that may change the management of this disease.

Key words

pheochromocytoma - paraganglioma - tyrosine kinase inhibitors - hypoxia inducible factors

References

• 1 Beard CM, Sheps SG, Kurland LT, Carney JA, Lie JT. Occurrence of pheochromocytoma in Rochester, Minnesota, 1950 through 1979.  Mayo Clinic proceedings. 1983;  58 802-804
• 2 Stenstrom G, Svardsudd K. Pheochromocytoma in Sweden 1958–1981 An analysis of the National Cancer Registry Data.  Acta medica Scandinavica. 1986;  220 225-232
• 3 MacNeil AR, Blok BH, Koelmeyer TD, Burke MP, Hilton JM. Phaeochromocytomas discovered during coronial autopsies in Sydney, Melbourne and Auckland.  Australian and New Zealand journal of medicine. 2000;  30 648-652
• 4 Mantero F, Terzolo M, Arnaldi G, Osella G, Masini AM, Ali A, Giovagnetti M, Opocher G, Angeli A. A survey on adrenal incidentaloma in Italy. Study group on adrenal tumors of the Italian society of Endocrinology.  The Journal of clinical endocrinology and metabolism. 2000;  85 637-644
• 5 Sutton MG, Sheps SG, Lie JT. Prevalence of clinically unsuspected pheochromocytoma. Review of a 50-year autopsy series.  Mayo Clinic proceedings. 1981;  56 354-360
• 6 van Heerden JA, Sheps SG, Hamberger B, Sheedy 2nd PF, Poston JG, ReMine WH. Pheochromocytoma: current status and changing trends.  Surgery. 1982;  91 367-373
• 7 Pham TH, Moir C, Thompson GB, Zarroug AE, Hamner CE, Farley D, van Heerden J, Lteif AN, Young Jr WF. Pheochromocytoma and paraganglioma in children: a review of medical and surgical management at a tertiary care center.  Pediatrics. 2006;  118 1109-1117
• 8 van Heerden JA, Roland CF, Carney JA, Sheps SG, Grant CS. Long-term evaluation following resection of apparently benign pheochromocytoma(s)/paraganglioma(s).  World J Surg. 1990;  14 325-329
• 9 Goldstein RE, O'Neill  Jr JA, Holcomb  3rd GW, Morgan  3rd WM, Neblett   3rd WW, Oates JA, Brown N, Nadeau J, Smith B, Page DL, Abumrad NN, Scott  Jr HW, Holcomb  3rd GW. Clinical experience over 48 years with pheochromocytoma.  Ann Surg. 1999;  229 755-764 , discussion 764-756
• 10 Kebebew E, Duh QY. Benign and malignant pheochromocytoma: diagnosis, treatment, and follow-up.  Surg Oncol Clin N Am. 1998;  7 765-789
• 11 John H, Ziegler WH, Hauri D, Jaeger P. Pheochromocytomas: can malignant potential be predicted?.  Urology. 1999;  53 679-683
• 12 Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Crespin M, Nau V, Khau Van, Kien P, Corvol P, Plouin PF, Jeunemaitre X. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas.  Cancer research. 2003;  63 5615-5621
• 13 Neumann HP, Pawlu C, Peczkowska M, Bausch B, MacWhinney SR, Muresan M, Buchta M, Franke G, Klisch J, Bley TA, Hoegerle S, Boedeker CC, Opocher G, Schipper J, Januszewicz A, Eng C. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations.  Jama. 2004;  292 943-951
• 14 Havekes B, Corssmit EP, Jansen JC, Mey van der AG, Vriends AH, Romijn JA. Malignant paragangliomas associated with mutations in the succinate dehydrogenase D gene.  The Journal of clinical endocrinology and metabolism. 2007;  92 1245-1248
• 15 Fritz A, Walch A, Piotrowska K, Rosemann M, Schaffer E, Weber K, Timper A, Wildner G, Graw J, Hofler H, Atkinson MJ. Recessive transmission of a multiple endocrine neoplasia syndrome in the rat.  Cancer research. 2002;  62 3048-3051
• 16 Pellegata NS, Quintanilla-Martinez L, Siggelkow H, Samson E, Bink K, Hofler H, Fend F, Graw J, Atkinson MJ. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans.  Proceedings of the National Academy of Sciences of the United States of America. 2006;  103 15558-15563
• 17 Pellegata NS, Quintanilla-Martinez L, Keller G, Liyanarachchi S, Hofler H, Atkinson MJ, Fend F. Human pheochromocytomas show reduced p27Kip1 expression that is not associated with somatic gene mutations and rarely with deletions.  Virchows Arch. 2007;  451 37-46
• 18 Eisenhofer G, Siegert G, Kotzerke J, Bornstein SR, Pacak K. Current progress and future challenges in the biochemical diagnosis and treatment of pheochromocytomas and paragangliomas.  Horm Metab Res. 2008;  40 329-337
• 19 Averbuch SD, Steakley CS, Young RC, Gelmann EP, Goldstein DS, Stull R, Keiser HR. Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine.  Annals of internal medicine. 1988;  109 267 273
• 20 Huang H, Abraham J, Hung E, Averbuch S, Merino M, Steinberg SM, Pacak K, Fojo T. Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: recommendation from a 22-year follow-up of 18 patients.  Cancer. 2008;  113 2020-2028
• 21 Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Glabbeke Van M, Oosterom van AT, Christian MC, Gwyther SG. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.  Journal of the National Cancer Institute. 2000;  92 205-216
• 22 Fitoussi O, Debled M, Masson B, Coindre JM, Kantor G, Bui BN. Brief report: Advanced paraganglioma: A role for chemotherapy?.  Medical and pediatric oncology. 1999;  33 129-131
• 23 Chrisoulidou A, Kaltsas G, Ilias I, Grossman AB. The diagnosis and management of malignant phaeochromocytoma and paraganglioma.  Endocrine-related cancer. 2007;  14 569-585
• 24 Pipas JM, Krywicki RF. Treatment of progressive metastatic glomus jugulare tumor (paraganglioma) with gemcitabine.  Neuro-oncology. 2000;  2 190-191
• 25 Kruijtzer CM, Beijnen JH, Swart M, Schellens JH. Successful treatment with paclitaxel of a patient with metastatic extra-adrenal pheochromocytoma (paraganglioma). A case report and review of the literature.  Cancer chemotherapy and pharmacology. 2000;  45 428-431
• 26 Schlumberger M, Gicquel C, Lumbroso J, Tenenbaum F, Comoy E, Bosq J, Fonseca E, Ghillani PP, Aubert B, Travagli JP. Malignant pheochromocytoma: clinical, biological, histologic and therapeutic data in a series of 20 patients with distant metastases.  Journal of endocrinological investigation. 1992;  15 631-642
• 27 Safford SD, Coleman RE, Gockerman JP, Moore J, Feldman JM, Leight  Jr GS, Tyler DS, Olson  Jr JA. Iodine -131 metaiodobenzylguanidine is an effective treatment for malignant pheochromocytoma and paraganglioma.  Surgery. 2003;  134 956-962 , discussion 962-953
• 28 Sisson JC, Shapiro B, Beierwaltes WH, Glowniak JV, Nakajo M, Mangner TJ, Carey JE, Swanson DP, Copp JE, Satterlee WG. Radiopharmaceutical treatment of malignant pheochromocytoma.  J Nucl Med. 1984;  25 197-206
• 29 Shapiro B, Sisson JC, Wieland DM, Mangner TJ, Zempel SM, Mudgett E, Gross MD, Carey JE, Zasadny KR, Beierwaltes WH. Radiopharmaceutical therapy of malignant pheochromocytoma with [131I]metaiodobenzylguanidine: results from ten years of experience.  J Nucl Biol Med. 1991;  35 269-276
• 30 Loh KC, Fitzgerald PA, Matthay KK, Yeo PP, Price DC. The treatment of malignant pheochromocytoma with iodine-131 metaiodobenzylguanidine (131I-MIBG): a comprehensive review of 116 reported patients.  Journal of endocrinological investigation. 1997;  20 648-658
• 31 Krempf M Lumbroso J, Mornex R, Brendel AJ, Wemeau JL, Delisle MJ, Aubert B, Carpentier P, Fleury-Goyon MC, Gibold C. Use of m-[131I]iodobenzylguanidine in the treatment of malignant pheochromocytoma.  The Journal of clinical endocrinology and metabolism. 1991;  72 455-461
• 32 Rose B, Matthay KK, Price D, Huberty J, Klencke B, Norton JA, Fitzgerald PA. High-dose 131I-metaiodobenzylguanidine therapy for 12 patients with malignant pheochromocytoma.  Cancer. 2003;  98 239-248
• 33 Limone P, Pogliano G, Castellano G, Argiro G, Isaia GC, Favero A, Cottino F, Rizzi G, Molinatti GM. 131-I-meta-iodobenzylguanidine for the diagnosis and treatment of pheochromocytoma.  Panminerva Med. 1988;  30 169-172
• 34 Konings JE, Bruning PF, Abeling NG, Gennip van AH, Hoefnagel CA. Diagnosis and treatment of malignant pheochromocytoma with 131I-meta-iodobenzylguanidine: a case report.  Radiother Oncol. 1990;  17 103-108
• 35 Kaltsas GA MJ, Foley R, Britton KE, Grossman AB. Treatment of Metastatic Pheochromocytoma and Paraganglioma With 131I-Meta-Iodobenzylguanidine (MIBG).  The Endocrinologist. 2003;  13 321-333
• 36 Owens J Bolster AA, Prosser JE, Cunningham S, Mairs RJ, Neilly JB, Reed NS, Hilditch TE. No-carrier-added 123I-MIBG: an initial clinical study in patients with phaeochromocytoma.  Nuclear medicine communications. 2000;  21 437-440
• 37 Ahlman H. Malignant pheochromocytoma: state of the field with future projections.  Annals of the New York Academy of Sciences. 2006;  1073 449-464
• 38 Forrer F, Riedweg I, Maecke HR, Mueller-Brand J. Radiolabeled DOTATOC in patients with advanced paraganglioma and pheochromocytoma.  Q J Nucl Med Mol Imaging. 2008;  52 334-340
• 39 Bryant J, Farmer J, Kessler LJ, Townsend RR, Nathanson KL. Pheochromocytoma: the expanding genetic differential diagnosis.  Journal of the National Cancer Institute. 2003;  95 1196-1204
• 40 Dahia PL, Ross KN, Wright ME, Hayashida CY, Santagata S, Barontini M, Kung AL, Sanso G, Powers JF, Tischler AS, Hodin R, Heitritter S, Moore F, Dluhy R, Sosa JA, Ocal IT, Benn DE, Marsh DJ, Robinson BG, Schneider K, Garber J, Arum SM, Korbonits M, Grossman A, Pigny P, Toledo SP, Nose V, Li C, Stiles CD. A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas.  PLoS genetics. 2005;  1 72-80
• 41 Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis.  Nature. 1998;  394 485-490
• 42 Baysal BE. On the association of succinate dehydrogenase mutations with hereditary paraganglioma.  Trends in endocrinology and metabolism: TEM. 2003;  14 453-459
• 43 Eng C, Kiuru M, Fernandez MJ, Aaltonen LA. A role for mitochondrial enzymes in inherited neoplasia and beyond.  Nature reviews. 2003;  3 193-202
• 44 Gimenez-Roqueplo AP, Favier J, Rustin P, Mourad JJ, Plouin PF, Corvol P, Rotig A, Jeunemaitre X. The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway.  American journal of human genetics. 2001;  69 1186-1197
• 45 Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Kerlan V, Plouin PF, Rotig A, Jeunemaitre X. Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma.  The Journal of clinical endocrinology and metabolism. 2002;  87 4771-4774
• 46 Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, Pan Y, Simon MC, Thompson CB, Gottlieb E. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase.  Cancer cell. 2005;  7 77-85
• 47 Kaelin  Jr WG. The von hippel-lindau tumor suppressor protein: an update.  Methods in enzymology. 2007;  435 371-383
• 48 Kaelin  Jr WG. The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer.  Nature reviews. 2008;  8 865-873
• 49 Semenza GL. Hypoxia-inducible factor 1 and cancer pathogenesis.  IUBMB life. 2008;  60 591-597
• 50 Hinze R, Machens A, Schneider U, Holzhausen HJ, Dralle H, Rath FW. Simultaneously occurring liver metastases of pheochromocytoma and medullary thyroid carcinoma – a diagnostic pitfall with clinical implications for patients with multiple endocrine neoplasia type 2a.  Pathology, research and practice. 2000;  196 477-481
• 51 Chevinsky AH, Minton JP, Falko JM. Metastatic pheochromocytoma associated with multiple endocrine neoplasia syndrome type II.  Arch Surg. 1990;  125 935-938
• 52 Scopsi L, Castellani MR, Gullo M, Cusumano F, Camerini E, Pasini B, Orefice S. Malignant pheochromocytoma in multiple endocrine neoplasia type 2B syndrome Case report and review of the literature.  Tumori. 1996;  82 480-484
• 53 Reed N, Gutmann DH. Tumorigenesis in neurofibromatosis: new insights and potential therapies.  Trends in molecular medicine. 2001;  7 157-162
• 54 Shen MH, Harper PS, Upadhyaya M. Molecular genetics of neurofibromatosis type 1 (NF1).  Journal of medical genetics. 1996;  33 2-17
• 55 Jimenez C, Cabanillas ME, Santarpia L, Jonasch E, Kyle KL, Lano EA, Matin SF, Nunez RF, Perrier ND, Phan A, Rich TA, Shah B, Williams MD, Waguespack SG. Use of the Tyrosine Kinase Inhibitor Sunitinib in a Patient with von Hippel-Lindau Disease: Targeting Angiogenic Factors in Pheochromocytoma and other von Hippel-Lindau Disease-related Tumors.  The Journal of clinical endocrinology and metabolism. 2009;  94 386-391
• 56 Joshua AM, Ezzat S, Asa SL, Evans A, Broom R, Freeman M, Knox JJ. Rationale and evidence for sunitinib in the treatment of malignant paraganglioma/pheochromocytoma.  J Clin Endocrinol Metabolism. 2009;  94 5-9
• 57 Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and response criteria of the Eastern Cooperative Oncology Group.  American journal of clinical oncology. 1982;  5 649-655
• 58 Welsh SJ, Williams RR, Birmingham A, Newman DJ, Kirkpatrick DL, Powis G. The thioredoxin redox inhibitors 1-methylpropyl 2-imidazolyl disulfide and pleurotin inhibit hypoxia-induced factor 1alpha and vascular endothelial growth factor formation.  Molecular cancer therapeutics. 2003;  2 235-243
• 59 Welsh S, Williams R, Kirkpatrick L, Paine-Murrieta G, Powis G. Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1alpha.  Molecular cancer therapeutics. 2004;  3 233-244
• 60 Lee S, Nakamura E, Yang H, Wei W, Linggi MS, Sajan MP, Farese RV, Freeman RS, Carter BD, Kaelin  Jr WG. Schlisio S. Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer.  Cancer cell. 2005;  8 155-167
• 61 Temes E, Martin-Puig S, Acosta-Iborra B, Castellanos MC, Feijoo-Cuaresma M, Olmos G, Aragones J, Landazuri MO. Activation of HIF-prolyl hydroxylases by R59949, an inhibitor of the diacylglycerol kinase.  The Journal of biological chemistry. 2005;  280 24238-24244
• 62 Choi HJ, Song BJ, Gong YD, Gwak WJ, Soh Y. Rapid degradation of hypoxia-inducible factor-1alpha by KRH102053, a new activator of prolyl hydroxylase 2.  British journal of pharmacology. 2008;  154 114-125
• 63 Jiang BH, Jiang G, Zheng JZ, Lu Z, Hunter T, Vogt P. Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1.  Cell Growth Differ. 2001;  12 363-369
• 64 Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ, Abraham RT. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin.  Molecular and cellular biology. 2002;  22 7004-7014
• 65 Sang N, Stiehl DP, Bohensky J, Leshchinsky I, Srinivas V, Caro J. MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300.  The Journal of biological chemistry. 2003;  278 14013-14019
• 66 Acker T, Diez-Juan A, Aragones J, Tjwa M, Brusselmans K, Moons L, Fukumura D, Moreno-Murciano MP, Herbert JM, Burger A, Riedel J, Elvert G, Flamme I, Maxwell PH, Collen D, Dewerchin M, Jain RK, Plate KH, Carmeliet P. Genetic evidence for a tumor suppressor role of HIF-2alpha.  Cancer cell. 2005;  8 131-141
• 67 Akiyama T, Sudo C, Ogawara H, Toyoshima K, Yamamoto T. The product of the human c-erbB-2 gene: a 185-kilodalton glycoprotein with tyrosine kinase activity.  Science (New York, NY. 1986;  232 1644-1646
• 68 Dragowska WH, Warburton C, Yapp DT, Minchinton AI, Hu Y, Waterhouse DN, Gelmon K, Skov K, Woo J, Masin D, Huxham LA, Kyle AH, Bally MB. HER-2/neu overexpression increases the viable hypoxic cell population within solid tumors without causing changes in tumor vascularization.  Mol Cancer Res. 2004;  2 606-619
• 69 Lai EW, Rodriguez OC, Aventian M, Cromelin C, Fricke ST, Martiniova L, Lubensky IA, Lisanti MP, Picard KL, Powers JF, Tischler AS, Pacak K, Albanese C. ErbB-2 induces bilateral adrenal pheochromocytoma formation in mice.  Cell cycle (Georgetown, Tex. 2007;  6 1946-1950
• 70 Yuan W, Wang W, Cui B, Su T, Ge Y, Jiang L, Zhou W, Ning G. Overexpression of ERBB-2 was more frequently detected in malignant than benign pheochromocytomas by multiplex ligation-dependent probe amplification and immunohistochemistry.  Endocrine-related cancer. 2008;  15 343-350
• 71 Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.  The New England journal of medicine. 2001;  344 783-792

Correspondence