Metastatic Phaeochromocytoma: Spinning Towards More Promising Treatment Options

Abstract

Phaeochromocytomas (PCC) and paragangliomas (PGL) are rare tumours arising from the chromaffin cells of the adrenal medulla (PCC) or the paraganglia located outside the adrenal gland (PGL). However, their incidence is likely to be underestimated; around 10% of all PCC/PGL are metastatic, with higher metastatic potential of PGLs compared to PCCs. If benign, surgery is the treatment of choice, but if metastatic, therapy is challenging. Here we review the currently existing therapy options for metastatic PCCs/PGLs including conventional chemotherapy (the original Averbuch scheme, but updated), radiopharmaceutical treatments (¹³¹I-MIBG, ⁹⁰Y- and ¹⁷⁷Lu-DOTATATE) and novel targeted therapies (anti-angiogenic tyrosine kinase inhibitors and mTORC1 inhibitors), emphasising future therapeutic approaches (HIF-2α and PARP inhibitors, temozolomide alone, metronomic temozolomide, somatostatin analogues) based on the oncogenic signalling pathways related to three different clusters comprising more than 20 well-characterised PCC/PGL susceptibility genes. We suggest that targeted combination therapies including repurposed agents may offer more effective future options worthy of exploration.

Key words

Malignant phaeochromocytoma - therapy - oncogenic signalling

• References

• 1 Beard CM, Sheps SG, Kurland LT. et al. Occurrence of pheochromocytoma in Rochester, Minnesota, 1950 through 1979. Mayo Clin Proc 1983; 58: 802-804
• 2 Barontini M, Levin G, Sanso G. Characteristics of pheochromocytoma in a 4- to 20-year-old population. Ann NY Acad Sci 2006; 1073: 30-37
• 3 Beltsevich DG, Kuznetsov NS, Kazaryan AM. et al. Pheochromocytoma surgery: epidemiologic peculiarities in children. World J Surg 2004; 28: 592-596
• 4 Sutton MG, Sheps SG, Lie JT. Prevalence of clinically unsuspected pheochromocytoma. Review of a 50-year autopsy series. Mayo Clin Proc 1981; 56: 354-360
• 5 Crona J, Taieb D, Pacak K. New Perspectives on pheochromocytoma and paraganglioma: Toward a molecular classification. Endocr Rev 2017; 38: 489-515
• 6 Korevaar TI, Grossman AB. Pheochromocytomas and paragangliomas: assessment of malignant potential. Endocrine 2011; 40: 354-365
• 7 Thompson LD. Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases. Am J Surg Pathol 2002; 26: 551-566
• 8 Strong VE, Kennedy T, Al-Ahmadie H. et al. Prognostic indicators of malignancy in adrenal pheochromocytomas: clinical, histopathologic, and cell cycle/apoptosis gene expression analysis. Surgery 2008; 143: 759-768
• 9 Liu TH, Chen YJ, Wu SF. et al. [Distinction between benign and malignant pheochromocytomas]. Zhonghua Bing Li Xue Za Zhi 2004; 33: 198-202
• 10 Lam AK. Update on Adrenal Tumours in 2017 World Health Organization (WHO) of Endocrine Tumours. Endocr Pathol. 2017. 28 213-227
• 11 O'Riordain DS, Young Jr. WF, Grant CS. et al. Clinical spectrum and outcome of functional extraadrenal paraganglioma. World J Surg 1996; 20: 916-921 discussion 922
• 12 Amar L, Bertherat J, Baudin E. et al. Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 2005; 23: 8812-8818
• 13 King KS, Prodanov T, Kantorovich V. et al. Metastatic pheochromocytoma/paraganglioma related to primary tumor development in childhood or adolescence: significant link to SDHB mutations. J Clin Oncol 2011; 29: 4137-4142
• 14 Grossman A, Pacak K, Sawka A. et al. Biochemical diagnosis and localization of pheochromocytoma: can we reach a consensus?. Ann NY Acad Sci 2006; 1073: 332-347
• 15 Eisenhofer G, Lenders JW, Siegert G. et al. Plasma methoxytyramine: a novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status. Eur J Cancer 2012; 48: 1739-1749
• 16 Parenti G, Zampetti B, Rapizzi E. et al. Updated and new perspectives on diagnosis, prognosis, and therapy of malignant pheochromocytoma/paraganglioma. J Oncol 2012; 2012: 872713
• 17 Jochmanova I, Pacak K. Genomic Landscape of pheochromocytoma and paraganglioma. Trends Cancer 2018; 4: 6-9
• 18 Fishbein L, Leshchiner I, Walter V. et al. Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell 2017; 31: 181-193
• 19 Roman-Gonzalez A, Zhou S, Ayala-Ramirez M. et al. Impact of surgical resection of the primary tumor on overall survival in patients with metastatic pheochromocytoma or sympathetic paraganglioma. Ann Surg 2017;
• 20 Roman-Gonzalez A, Jimenez C. Malignant pheochromocytoma-paraganglioma: pathogenesis, TNM staging, and current clinical trials. Curr Opin Endocrinol Diabetes Obes 2017; 24: 174-183
• 21 Wei S, Wu D, Yue J. Surgical resection of multiple liver metastasis of functional malignant pheochromocytoma: a case report and literature review. J Cancer Res Ther 2013; 9 Suppl: S183-S185
• 22 Arnas-Leon C, Sanchez V, Santana Suarez AD. et al. Complete remission in metastatic pheochromocytoma treated with extensive surgery. Cureus 2016; 8: e447
• 23 Ellis RJ, Patel D, Prodanov T. et al. Response after surgical resection of metastatic pheochromocytoma and paraganglioma: can postoperative biochemical remission be predicted?. J Am Coll Surg 2013; 217: 489-496
• 24 Averbuch SD, Steakley CS, Young RC. et al. Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Ann Intern Med 1988; 109: 267-273
• 25 Angelousi A, Dimitriadis GK, Zografos G. et al. Molecular targeted therapies in adrenal, pituitary and parathyroid malignancies. Endocr Relat Cancer 2017; 24: R239-R259
• 26 Jochmanova I, Yang C, Zhuang Z. et al. Hypoxia-inducible factor signaling in pheochromocytoma: turning the rudder in the right direction. J Natl Cancer Inst 2013; 105: 1270-1283
• 27 Tella SH, Taieb D, Pacak K. HIF-2alpha: Achilles' heel of pseudohypoxic subtype paraganglioma and other related conditions. Eur J Cancer 2017; 86: 1-4
• 28 Comino-Mendez I, Gracia-Aznarez FJ, Schiavi F. et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nature Genetics 2011; 43: 663-667
• 29 Gimenez-Roqueplo AP, Favier J, Rustin P. et al. Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma. J Clin Endocrinol Metab 2002; 87: 4771-4774
• 30 Gimenez-Roqueplo AP, Favier J, Rustin P. et al. 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. Am J Hum Genet 2001; 69: 1186-1197
• 31 Pollard PJ, El-Bahrawy M, Poulsom R. et al. Expression of HIF-1alpha, HIF-2alpha (EPAS1), and their target genes in paraganglioma and pheochromocytoma with VHL and SDH mutations. J Clin Endocrinol Metab 2006; 91: 4593-4598
• 32 Pollard PJ, Briere JJ, Alam NA. et al. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet 2005; 14: 2231-2239
• 33 Favier J, Briere JJ, Burnichon N. et al. The Warburg effect is genetically determined in inherited pheochromocytomas. PLoS One 2009; 4: e7094
• 34 Koh MY, Lemos Jr. R, Liu X. et al. The hypoxia-associated factor switches cells from HIF-1alpha- to HIF-2alpha-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion. Cancer Res 2011; 71: 4015-4027
• 35 Zhuang Z, Yang C, Lorenzo F. et al. Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. N Engl J Med 2012; 367: 922-930
• 36 Lorenzo FR, Yang C, Ng Tang Fui M. et al. A novel EPAS1/HIF2A germline mutation in a congenital polycythemia with paraganglioma. J Mol Med (Berl) 2013; 91: 507-512
• 37 Pacak K, Jochmanova I, Prodanov T. et al. New syndrome of paraganglioma and somatostatinoma associated with polycythemia. J Clin Oncol 2013; 31: 1690-1698
• 38 Taieb D, Yang C, Delenne B. et al. First report of bilateral pheochromocytoma in the clinical spectrum of HIF2A-related polycythemia-paraganglioma syndrome. J Clin Endocrinol Metab 2013; 98: E908-E913
• 39 Comino-Mendez I, de Cubas AA, Bernal C. et al. Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis. Hum Mol Genet 2013; 22: 2169-2176
• 40 Toledo RA, Qin Y, Srikantan S. et al. In vivo and in vitro oncogenic effects of HIF2A mutations in pheochromocytomas and paragangliomas. Endocr Relat Cancer 2013; 20: 349-359
• 41 Mylonis I, Chachami G, Samiotaki M. et al. Identification of MAPK phosphorylation sites and their role in the localization and activity of hypoxia-inducible factor-1alpha. J Biol Chem 2006; 281: 33095-33106
• 42 Richard DE, Berra E, Gothie E. et al. p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1. J Biol Chem 1999; 274: 32631-32637
• 43 Lim JH, Lee ES, You HJ. et al. Ras-dependent induction of HIF-1alpha785 via the Raf/MEK/ERK pathway: a novel mechanism of Ras-mediated tumor promotion. Oncogene 2004; 23: 9427-9431
• 44 Mohlin S, Hamidian A, von Stedingk K. et al. PI3K-mTORC2 but not PI3K-mTORC1 regulates transcription of HIF2A/EPAS1 and vascularization in neuroblastoma. Cancer Res 2015; 75: 4617-4628
• 45 Elorza A, Soro-Arnaiz I, Melendez-Rodriguez F. et al. HIF2alpha acts as an mTORC1 activator through the amino acid carrier SLC7A5. Mol Cell 2012; 48: 681-691
• 46 Brugarolas J, Lei K, Hurley RL. et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 2004; 18: 2893-2904
• 47 Land SC, Tee AR. Hypoxia-inducible factor 1alpha is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif. J Biol Chem 2007; 282: 20534-20543
• 48 Gimenez-Roqueplo AP, Dahia PL, Robledo M. An update on the genetics of paraganglioma, pheochromocytoma, and associated hereditary syndromes. Horm Metab Res 2012; 44: 328-333
• 49 Fukuda R, Hirota K, Fan F. et al. Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. J Biol Chem 2002; 277: 38205-38211
• 50 Crona J, Delgado Verdugo A, Maharjan R. et al. Somatic mutations in H-RAS in sporadic pheochromocytoma and paraganglioma identified by exome sequencing. J Clin Endocrinol Metab 2013; 98: E1266-E1271
• 51 Kim WY, Perera S, Zhou B. et al. HIF2alpha cooperates with RAS to promote lung tumorigenesis in mice. J Clin Invest 2009; 119: 2160-2170
• 52 Sbardella E, Cranston T, Isidori AM. et al. Routine genetic screening with a multi-gene panel in patients with pheochromocytomas. Endocrine 2018; 59: 175-182
• 53 Remacha L, Curras-Freixes M, Torres-Ruiz R. et al. Gain-of-function mutations in DNMT3A in patients with paraganglioma. Genet Med 2018;
• 54 Grogan RH, Mitmaker EJ, Duh QY. Changing paradigms in the treatment of malignant pheochromocytoma. Cancer Control 2011; 18: 104-112
• 55 Jimenez P, Tatsui C, Jessop A. et al. Treatment for Malignant Pheochromocytomas and Paragangliomas: 5 Years of Progress. Curr Oncol Rep 2017; 19: 83
• 56 Keiser HR, Goldstein DS, Wade JL. et al. Treatment of malignant pheochromocytoma with combination chemotherapy. Hypertension 1985; 7 3 Pt 2 I18-I24
• 57 Niemeijer ND, Alblas G, van Hulsteijn LT. et al. Chemotherapy with cyclophosphamide, vincristine and dacarbazine for malignant paraganglioma and pheochromocytoma: systematic review and meta-analysis. Clin Endocrinol (Oxf) 2014; 81: 642-651
• 58 Ayala-Ramirez M, Feng L, Habra MA. et al. Clinical benefits of systemic chemotherapy for patients with metastatic pheochromocytomas or sympathetic extra-adrenal paragangliomas: insights from the largest single-institutional experience. Cancer 2012; 118: 2804-2812
• 59 Jimenez C, Rohren E, Habra MA. et al. Current and future treatments for malignant pheochromocytoma and sympathetic paraganglioma. Curr Oncol Rep 2013; 15: 356-371
• 60 Plouin PF, Fitzgerald P, Rich T. et al. Metastatic pheochromocytoma and paraganglioma: focus on therapeutics. Horm Metab Res 2012; 44: 390-399
• 61 Huang H, Abraham J, Hung E. et al. 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
• 62 Jawed I, Velarde M, Darr R. et al. Continued tumor reduction of metastatic pheochromocytoma/paraganglioma harboring succinate dehydrogenase subunit b mutations with cyclical chemotherapy. Cell Mol Neurobiol 2018;
• 63 Tay CG, Lee VWM, Ong LC et al. Vincristine-induced peripheral neuropathy in survivors of childhood acute lymphoblastic leukaemia. Pediatr Blood Cancer 2017; 64:
• 64 Hadoux J, Favier J, Scoazec JY. et al. SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma. Int J Cancer 2014; 135: 2711-2720
• 65 Pegg AE, Dolan ME, Moschel RC. Structure, function, and inhibition of O6-alkylguanine-DNA alkyltransferase. Prog Nucleic Acid Res Mol Biol 1995; 51: 167-223
• 66 Hegi ME, Liu L, Herman JG. et al. Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. J Clin Oncol 2008; 26: 4189-4199
• 67 Bignami M, O'Driscoll M, Aquilina G. et al. Unmasking a killer: DNA O(6)-methylguanine and the cytotoxicity of methylating agents. Mutat Res 2000; 462: 71-82
• 68 Tena I, Gupta G, Tajahuerce M. et al. Successful second-line metronomic temozolomide in metastatic paraganglioma: Case reports and review of the literature. Clin Med Insights Oncol 2018; 12: 1179554918763367
• 69 Gonias S, Goldsby R, Matthay KK. et al. Phase II study of high-dose [131I]metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma. J Clin Oncol 2009; 27: 4162-4168
• 70 Krempf M, Lumbroso J, Mornex R. et al. Treatment of malignant pheochromocytoma with [131I]metaiodobenzylguanidine: a French multicenter study. J Nucl Biol Med 1991; 35: 284-287
• 71 Loh KC, Fitzgerald PA, Matthay KK. et al. The treatment of malignant pheochromocytoma with iodine-131 metaiodobenzylguanidine (131I-MIBG): a comprehensive review of 116 reported patients. J Endocrinol Invest 1997; 20: 648-658
• 72 Mukherjee JJ, Kaltsas GA, Islam N. et al. Treatment of metastatic carcinoid tumours, phaeochromocytoma, paraganglioma and medullary carcinoma of the thyroid with (131)I-meta-iodobenzylguanidine [(131)I-mIBG]. Clin Endocrinol (Oxf) 2001; 55: 47-60
• 73 Sze WC, Grossman AB, Goddard I. et al. Sequelae and survivorship in patients treated with (131)I-MIBG therapy. Br J Cancer 2013; 109: 565-572
• 74 Basu S, Abhyankar A, Jatale P. The current place and indications of 131I-metaiodobenzylguanidine therapy in the era of peptide receptor radionuclide therapy: determinants to consider for evolving the best practice and envisioning a personalized approach. Nucl Med Commun 2015; 36: 1-7
• 75 van Hulsteijn LT, Niemeijer ND, Dekkers OM. et al. (131)I-MIBG therapy for malignant paraganglioma and phaeochromocytoma: systematic review and meta-analysis. Clin Endocrinol (Oxf) 2014; 80: 487-501
• 76 Nastos K, Cheung VTF, Toumpanakis C. et al. Peptide receptor radionuclide treatment and (131)I-MIBG in the management of patients with metastatic/progressive phaeochromocytomas and paragangliomas. J Surg Oncol 2017; 115: 425-434
• 77 Rose B, Matthay KK, Price D. et al. High-dose 131I-metaiodobenzylguanidine therapy for 12 patients with malignant pheochromocytoma. Cancer 2003; 98: 239-248
• 78 Barrett JA, Joyal JL, Hillier SM. et al. Comparison of high-specific-activity ultratrace 123/131I-MIBG and carrier-added 123/131I-MIBG on efficacy, pharmacokinetics, and tissue distribution. Cancer Biother Radiopharm 2010; 25: 299-308
• 79 Jimenez CPD, Sullivan DC, Schwarz JK et al. Long term follow-up of a pivotal phase 2 study of Ultratrace® Iobenguane I-131 (AZEDRA TM) in patients with malignant relapsed/refractory pheo- chromocytoma (pheo)/paraganglioma (para). In: Adrenal Tumors: Clinical Implications of the Recent Molecular and Genetic Findings;. Endocrine Society’s 97th Annual Meeting and Expo; 2015
• 80 Van Essen M, Krenning EP, De Jong M. et al. Peptide receptor radionuclide therapy with radiolabelled somatostatin analogues in patients with somatostatin receptor positive tumours. Acta Oncol 2007; 46: 723-734
• 81 Ziegler CG, Brown JW, Schally AV. et al. Expression of neuropeptide hormone receptors in human adrenal tumors and cell lines: antiproliferative effects of peptide analogues. Proc Natl Acad Sci USA 2009; 106: 15879-15884
• 82 van Essen M, Krenning EP, Kooij PP. et al. Effects of therapy with [177Lu-DOTA0, Tyr3]octreotate in patients with paraganglioma, meningioma, small cell lung carcinoma, and melanoma. J Nucl Med 2006; 47: 1599-1606
• 83 Zovato S, Kumanova A, Dematte S. et al. Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE in individuals with neck or mediastinal paraganglioma (PGL). Horm Metab Res 2012; 44: 411-414
• 84 Forrer F, Riedweg I, Maecke HR. et al. Radiolabeled DOTATOC in patients with advanced paraganglioma and pheochromocytoma. Q J Nucl Med Mol Imaging 2008; 52: 334-340
• 85 Kong G, Grozinsky-Glasberg S, Hofman MS. et al. Efficacy of peptide receptor radionuclide therapy for functional metastatic paraganglioma and pheochromocytoma. J Clin Endocrinol Metab 2017; 102: 3278-3287
• 86 Strosberg J, El-Haddad G, Wolin E. et al. Phase 3 trial of (177)lu-dotatate for midgut neuroendocrine tumors. N Engl J Med 2017; 376: 125-135
• 87 Vogel J, Atanacio AS, Prodanov T. et al. External beam radiation therapy in treatment of malignant pheochromocytoma and paraganglioma. Front Oncol 2014; 4: 166
• 88 Breen W, Bancos I, Young Jr. WF. et al. External beam radiation therapy for advanced/unresectable malignant paraganglioma and pheochromocytoma. Adv Radiat Oncol 2018; 3: 25-29
• 89 Patchell RA, Tibbs PA, Regine WF. et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet 2005; 366: 643-648
• 90 Sahgal A, Larson DA, Chang EL. Stereotactic body radiosurgery for spinal metastases: a critical review. Int J Radiat Oncol Biol Phys 2008; 71: 652-665
• 91 Wang XS, Rhines LD, Shiu AS. et al. Stereotactic body radiation therapy for management of spinal metastases in patients without spinal cord compression: a phase 1-2 trial. Lancet Oncol 2012; 13: 395-402
• 92 Yamada Y, Bilsky MH, Lovelock DM. et al. High-dose, single-fraction image-guided intensity-modulated radiotherapy for metastatic spinal lesions. Int J Radiat Oncol Biol Phys 2008; 71: 484-490
• 93 Ayala-Ramirez M, Chougnet CN, Habra MA. et al. Treatment with sunitinib for patients with progressive metastatic pheochromocytomas and sympathetic paragangliomas. J Clin Endocrinol Metab 2012; 97: 4040-4050
• 94 Druce MR, Kaltsas GA, Fraenkel M. et al. Novel and evolving therapies in the treatment of malignant phaeochromocytoma: experience with the mTOR inhibitor everolimus (RAD001). Hormone and Metabolic Research 2009; 41: 697-702
• 95 Nölting S, Maurer J, Spottl G. et al. Additive anti-tumor effects of lovastatin and everolimus in vitro through simultaneous inhibition of signaling pathways. PLoS One 2015; 10: e0143830
• 96 Nölting S, Garcia E, Alusi G. et al. Combined blockade of signalling pathways shows marked anti-tumour potential in phaeochromocytoma cell lines. Journal of Molecular Endocrinology 2012; 49: 79-96
• 97 Nölting S, Giubellino A, Tayem Y. et al. Combination of 13-cis retinoic acid and lovastatin: Marked anti-tumor potential in vivo in a pheochromocytoma allograft model in female athymic nude mice. Endocrinology 2014;
• 98 Giubellino A, Bullova P, Nolting S. et al. Combined inhibition of mTORC1 and mTORC2 signaling pathways is a promising therapeutic option in inhibiting pheochromocytoma tumor growth: in vitro and in vivo studies in female athymic nude mice. Endocrinology 2013; 154: 646-655
• 99 Choueiri TK, Halabi S, Sanford BL. et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: The Alliance A031203 CABOSUN Trial. J Clin Oncol 2017; 35: 591-597
• 100 Choueiri TK, Hessel C, Halabi S. et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): Progression-free survival by independent review and overall survival update. Eur J Cancer 2018; 94: 115-125
• 101 Smith M, De Bono J, Sternberg C. et al. Phase III Study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol 2016; 34: 3005-3013
• 102 Jasim S, Suman VJ, Jimenez C. et al. Phase II trial of pazopanib in advanced/progressive malignant pheochromocytoma and paraganglioma. Endocrine 2017; 57: 220-225
• 103 Nölting S, Grossman AB. Signaling pathways in pheochromocytomas and paragangliomas: prospects for future therapies. Endocr Pathol 2012; 23: 21-33
• 104 Cho H, Du X, Rizzi JP. et al. On-target efficacy of a HIF-2alpha antagonist in preclinical kidney cancer models. Nature 2016; 539: 107-111
• 105 Chen W, Hill H, Christie A. et al. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature 2016; 539: 112-117
• 106 Caplin ME, Pavel M, Cwikla JB. et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 2014; 371: 224-233
• 107 Rinke A, Muller HH, Schade-Brittinger C. et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 2009; 27: 4656-4663
• 108 Ray Chaudhuri A, Nussenzweig A. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat Rev Mol Cell Biol 2017; 18: 610-621
• 109 de Murcia JM, Niedergang C, Trucco C. et al. Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proc Natl Acad Sci U S A 1997; 94: 7303-7307
• 110 Ben-Hur E, Utsumi H, Elkind MM. Inhibitors of poly (ADP-ribose) synthesis enhance radiation response by differentially affecting repair of potentially lethal versus sublethal damage. Br J Cancer Suppl 1984; 6: 39-42
• 111 Schlicker A, Peschke P, Burkle A. et al. 4-Amino-1,8-naphthalimide: a novel inhibitor of poly(ADP-ribose) polymerase and radiation sensitizer. Int J Radiat Biol 1999; 75: 91-100
• 112 Pang Y, Lu Y, Caisova V. et al. Targeting NAD+/PARP DNA repair pathway as a novel therapeutic approach to SDHB-mutated cluster I pheochromocytoma and paraganglioma. Clin Cancer Res 2018;
• 113 Allegrezza MJ, Conejo-Garcia JR. Targeted therapy and immunosuppression in the tumor microenvironment. Trends Cancer 2017; 3: 19-27