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Therapeutic Targeting of SDHB-Mutated Pheochromocytoma

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Therapeutic Targeting of SDHB-Mutated Pheochromocytoma Author Manuscript Published OnlineFirst on March 9, 2020; DOI: 10.1158/1078-0432.CCR-19-2335 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Therapeutic targeting of SDHB-mutated pheochromocytoma/paraganglioma with 2 pharmacologic ascorbic acid 3 4 Yang Liu1*, Ying Pang2*, Boqun Zhu2,3, Ondrej Uher2,4, Veronika Caisova2, Thanh-Truc 5 Huynh2, David Taieb5, Katerina Hadrava Vanova6, Hans Kumar Ghayee7, Jiri Neuzil4,8, Mark 6 Levine9, Chunzhang Yang1#, and Karel Pacak2# 7 8 Author affiliation: 9 1Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, 10 Bethesda, Maryland 20892, USA 11 2Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child 12 Health and Human Development, NIH, Bethesda, Maryland 20892, USA 13 3Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, 14 Shanghai, 200032, PR China 15 4Department of Medical Biology, Faculty of Science, University of South Bohemia, Ceske 16 Budejovice, 370 05 Czech Republic 17 5Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille 18 University, 13385 Marseille, France 19 6Molecular Therapy Group, Institute of Biotechnology, Czech Academy of Sciences, Prague- 20 West, 252 50 Czech Republic 21 7Department of Internal Medicine, Division of Endocrinology, University of Florida College of 22 Medicine and Malcom Randall VA Medical Center, Gainesville, FL 32608, USA 23 8Mitochondria, Apoptosis and Cancer Research Group, School of Medical Science and Menzies 24 Health Institute Queensland, Griffith University, Southport, Queensland 4222, Australia 25 9Molecular and Clinical Nutrition Section, Intramural Research Program, National Institute of 26 Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA 27 28 29 *#Equal Contribution 30 31 Running title: Targeting ROS/labile iron overload pathway to treat SDHB-mutant PCPGs 32 33 Keywords: Pheochromocytoma/paraganglioma, SDHB mutations, reactive oxygen species, 34 ascorbic acid 35 36 Word count: 5,307 37 Number of figures: 6 and 3 supplementary 38 Number of tables: 2 supplementary 39 40 41 Corresponding author and person to whom reprint requests should be addressed: 42 43 Karel Pacak, M.D., Ph.D., D.Sc., FACE 44 Senior Investigator 45 Chief, Section on Clinical Neuroendocrinology 1 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 9, 2020; DOI: 10.1158/1078-0432.CCR-19-2335 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Head, Developmental Endocrinology, Metabolism, Genetics and Endocrine 2 Oncology Affinity Group 3 Professor of Medicine 4 Section on Medical Neuroendocrinology 5 Eunice Kennedy Shriver National Institute of Child Health and Human Development 6 Building 10, Room 1-3140, MSC 1109 7 10 Center Drive, Bethesda, MD 20892 8 Tel: (301) 402-4594 9 Fax: (301) 402-4712 10 e-mail: [email protected] 11 12 13 Chunzhang Yang, Ph.D. 14 Investigator 15 Neuro-Oncology Branch Center for Cancer Research, NCI, NIH 16 Building 37, Room 1142E Bethesda, MD 20892 17 Phone: +1-240-760-7083 18 e-mail: [email protected] 19 20 Disclosure Statement: The authors declare no potential conflicts of interest. 21 2 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 9, 2020; DOI: 10.1158/1078-0432.CCR-19-2335 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Statement of translational relevance: Readership should be interested in this paper 2 because it demonstrates that SDHB-low Cluster I PCPG cells exhibited pseudohypoxia, 3 which reprogramed iron homeostasis and consequently resulted in high ROS generation. 4 This effect was enhanced by pharmacologic concentrations of ascorbic acid, presenting a 5 new approach for treating these types of cancers. Ascorbic acid is currently a treatment 6 agent in several clinical trials for acute myeloid leukemia, metastatic prostate cancer, 7 metastatic colon cancer, advanced non-small-cell lung cancer, and glioblastoma. Because 8 pharmacologic ascorbic acid has an excellent clinical safety profile, it is likely that ascorbic 9 acid can be a valuable tool for the treatment of PCPGs as well, for which few therapeutic 10 options exist. 11 3 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 9, 2020; DOI: 10.1158/1078-0432.CCR-19-2335 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Abstract 2 Purpose: Pheochromocytomas and paragangliomas (PCPGs) are usually benign 3 neuroendocrine tumors. However, PCPGs with mutations in the succinate dehydrogenase B 4 subunit (SDHB) have a poor prognosis and frequently develop metastatic lesions. SDHB- 5 mutated PCPGs exhibit dysregulation in oxygen metabolic pathways, including 6 pseudohypoxia and formation of reactive oxygen species (ROS), suggesting that targeting 7 the redox balance pathway could be a potential therapeutic approach. 8 Experimental design: We studied the genetic alterations of Cluster I PCPGs compared to 9 Cluster II PCPGs, which usually present as benign tumors. By targeting the signature 10 molecular pathway, we investigated the therapeutic effect of ascorbic acid on PCPGs using 11 in vitro and in vivo models. 12 Results: By investigating PCPG cells with low SDHB levels, we show that pseudohypoxia 13 resulted in elevated expression of iron transport proteins, including transferrin (TF), 14 transferrin receptor 2 (TFR2) and the divalent metal transporter 1 (SLC11A2; DMT1), 15 leading to iron accumulation. This iron overload contributed to elevated oxidative stress. 16 Ascorbic acid at pharmacologic concentrations disrupted redox homeostasis, inducing DNA 17 oxidative damage, and cell apoptosis in PCPG cells with low SDHB levels. Besides, through a 18 preclinical animal model with PCPG allografts, we demonstrated that pharmacologic 19 ascorbic acid suppressed SDHB-low metastatic lesions and prolonged overall survival. 20 Conclusions: The data here demonstrate that targeting redox homeostasis as a cancer 21 vulnerability with pharmacologic ascorbic acid is a promising therapeutic strategy for 22 SDHB-mutated PCPGs. 4 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 9, 2020; DOI: 10.1158/1078-0432.CCR-19-2335 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Introduction 2 Pheochromocytomas and paragangliomas (PCPGs) are catecholamine-producing 3 tumors, which are stratified into two major molecular subtypes: cluster I and cluster II. 4 Cluster I PCPGs, commonly exhibit abnormal activation of hypoxia signaling, particularly 5 those carrying mutations in succinate dehydrogenase subunits (SDHx), von Hippel-Lindau 6 (VHL), hypoxia-inducible factor 2A (HIF2A) or fumarate hydratase (FH). Cluster II PCPGs 7 commonly show hyperactivation of protein kinase pathways, carry mutations in ret proto- 8 oncogene (RET), neurofibromatosis type 1 (NF1), MYC associated factor X (MAX), 9 transmembrane protein 127 (TMEM127) or the kinesin family member 1B (KIF1B) (1-3). 10 Succinate dehydrogenase (SDH), also known as the mitochondrial respiratory complex II, 11 comprises SDHA, SDHB, SDHC, and SDHD subunits (4). Loss-of-function mutations in SDHx 12 lead to substantial loss of the complex II activity and results in reprogramming of cellular 13 metabolic pathways, as indicated by the accumulation of succinate, genome-wide 14 hypermethylation and a pseudohypoxia phenotype (5-10). Further, compromised complex 15 II disrupts electron transfer to oxygen, leading to increased formation of reactive oxygen 16 species (ROS) and redox imbalance (11,12). 17 Clinically, SDHB deficient PCPGs are one of the most common subtypes of Cluster I 18 PCPGs. In contrast to other PCPGs molecular subtypes, SDHB deficient PCPGs, especially 19 those producing and secreting catecholamines/metanephrines, typically present an early 20 onset and display tumor aggressiveness with development of metastases, all resulting in 21 patient mortality (13-16). For advanced PCPGs with metastatic lesions, surgical resection 22 coupled to radio- or chemotherapies are considered the standards of care. For 23 chemotherapy, the most widely used regimen is a combination of cyclophosphamide, 5 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 9, 2020; DOI: 10.1158/1078-0432.CCR-19-2335 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 vincristine, and dacarbazine (CVD regimen) (17). However, emerging evidence shows that 2 in some patients, the CVD regimen produces only transient effects with only minimally 3 prolonged overall patient survival (18). Therefore, therapeutic approaches with enhanced 4 efficacy have been advocated to better handle advanced PCPGs. 5 The pseudohypoxic ‘signature’ and angiogenic pathways have been proposed as 6 targets for limiting tumor expansion in Cluster I PCPGs (19). Humanized monoclonal
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