TY - JOUR
T1 - Somatostatin receptor 2 expression in nasopharyngeal cancer is induced by Epstein Barr virus infection: impact on prognosis, imaging and therapy
AU - Lechner, M.
AU - Schartinger, V.H.
AU - Steele, C.D.
AU - Nei, W.L.
AU - Ooft, M.L.
AU - Schreiber, L.M.
AU - Pipinikas, C.P.
AU - Chung, G.T.Y.
AU - Chan, Y.Y.
AU - Wu, F.
AU - To, K.F.
AU - Tsang, C.M.
AU - Pearce, W.
AU - Morelli, D.
AU - Philpott, M.
AU - Masterson, L.
AU - Nibhani, R.
AU - Wells, G.
AU - Bell, C.G.
AU - Koller, J.
AU - Delecluse, S.
AU - Yip, Y.L.
AU - Liu, J.
AU - Forde, C.T.
AU - Forster, M.D.
AU - Jay, A.
AU - Dudas, J.
AU - Krapp, A.
AU - Wan, S.
AU - Uprimny, C.
AU - Sprung, S.
AU - Haybaeck, J.
AU - Fenton, T.R.
AU - Chester, K.
AU - Thirlwell, C.
AU - Royle, G.
AU - Marafioti, T.
AU - Gupta, R.
AU - Indrasari, S.R.
AU - Herdini, C.
AU - Slim, M.A.M.
AU - Indrawati, I.
AU - Sutton, L.
AU - Fles, R.
AU - Tan, B.
AU - Jain, A.
AU - Han, S.T.
AU - Wang, H.T.
AU - Loke, K.S.H.
AU - Lund, V.
AU - Van Haesbroeck, Bart
AU - Lund, Valerie J.
N1 - Funding Information:
This research work was funded by the Rhinology and Laryngology Research Fund, Royal College of Surgeons (Colledge Family Research Grant), UCL/UCLH Biomedical Research Centre (BRC), the Association for the Global Advancement of ENT Surgery and Head and Neck Cancer Research (AGA-ENT), the Austrian Science Foundation (FWF grant: I 3976-B33) and the Christian Doppler Research Association. Research reported in this publication was jointly supported by the ASEAN-European Academic University Network (ASEA-UNINET), the Austrian Federal Ministry of Education, Science and Research and the Austrian Agency for International Cooperation in Education and Research (OeAD-GmbH). We would like to acknowledge the invaluable support from Prof. Tariq Enver via the UCL Shenzhen collaboration and the UCL Cancer Institute. We would also like to thank Josep Linares, Dr. Naomi Guppy and David Allan from HSL Labs/UCL Advanced Diagnostics, and Dr. Mathew J. Garnett from the Cancer Genome Project, Wellcome Trust Sanger Institute for his advice and help with optimizing the in vitro drug-screening experiments. We would also like to thank Ellen Richter from the Christian Doppler lab for excellent technical assistance. We would like to thank Dr. Kerry Whalen and Richard Wooster from Tarveda Therapeutics, who supplied us with the drug-conjugate PEN-221 for in vitro and in vivo testing. We would like to thank Prof. Ova Emilia and Prof. Md. Hakimi for their support at UGM, Staff and colleagues from the Division of Anatomical Pathology, the Department of Nuclear Medicine and Molecular Imaging at Singapore General Hospital, the Head and Neck Team National Cancer Center Singapore, Dr Tan Min Han and team from A*STAR Institute of Bioengineering and Nanotechnology, Prof. Dr. Wolfgang Freysinger from the Medical University of Innsbruck, Prof Dr. Felix Offner from the LKH Feldkirch. Dr. Charles Breeze for his help with molecular data and Research Services at UCL and the UCL Ethics Committee. Research in the laboratory of B.V. is supported by Cancer Research UK (C23338/A25722) and the UK NIHR University College London Hospitals Biomedical Research Centre. N.P. is funded through a Cancer Research UK clinician scientist fellowship (Award reference: 18387). C.S. is funded by Cancer Research UK. Dr. Kwok-Wai Lo is supported by the Research Grants Council (RGC) of Hong Kong (T1-2‐401/13‐R; C4001-18GF; C7027-16G; C5012-15E; 14117316). M.L.K.C. is supported by the National Medical Research Council Singapore Clinician-Scientist Award - #NMRC/CSA/0027/2018, the Duke-NUS Oncology Academic Program Proton Research Program, and the National Research Foundation Clinical Research Program Grant (NRF-CRP17-2017-05). W.L.N. is supported by the National Medical Research Council Singapore Research Training Fellowship and the National Cancer Center Singapore Research Fund.
Funding Information:
B.V. is a consultant for Venthera (Palo Alto, US), iOnctura (Geneva, Switzerland) and Karus Therapeutics, Oxford, UK and has received speaker’s fees from Gilead (Foster City, US). T.Me. has acted as a consultant for Tarveda Therapeutics (Watertown, MA, US). G. W. serves as a scientific advisor to ViraTherapeutics and Boehringer Ingelheim. S.M. receives research grants from Pfizer, Bayer, MSD, AstraZeneca, Nextcure, Roche, BMS, Amgen and Lily. M.C. reports personal fees from Astellas, personal fees from Janssen, grants and personal fees from Ferring, personal fees from MSD Oncology, personal fees from Illumina, nonfinancial support from AstraZeneca, personal fees and nonfinancial support from Varian, nonfinancial support from GenomeDx Biosciences, nonfinancial support from Medlever, outside the submitted work. All other authors declare no competing interests.
Funding Information:
Work in U.O.’s laboratory was supported by the LEAN Network from the Leducq Foundation, NIHR BRC Oxford, CRUK and from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA grant agreement no. [609305]. Q.L.E. is supported by R01 DE025227 (NIDCR/NIH). S.W.T. was supported by grants GRF 106180141, CRF C7027-16G, and HRF260870784 for the establishments of the NPC cell lines.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/1/5
Y1 - 2021/1/5
N2 - Nasopharyngeal cancer (NPC), endemic in Southeast Asia, lacks effective diagnostic and therapeutic strategies. Even in high-income countries the 5-year survival rate for stage IV NPC is less than 40%. Here we report high somatostatin receptor 2 (SSTR2) expression in multiple clinical cohorts comprising 402 primary, locally recurrent and metastatic NPCs. We show that SSTR2 expression is induced by the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) via the NF-kappa B pathway. Using cell-based and preclinical rodent models, we demonstrate the therapeutic potential of SSTR2 targeting using a cytotoxic drug conjugate, PEN-221, which is found to be superior to FDA-approved SSTR2-binding cytostatic agents. Furthermore, we reveal significant correlation of SSTR expression with increased rates of survival and report in vivo uptake of the SSTR2-binding Ga-68-DOTA-peptide radioconjugate in PET-CT scanning in a clinical trial of NPC patients (NCT03670342). These findings reveal a key role in EBV-associated NPC for SSTR2 in infection, imaging, targeted therapy and survival. Nasopharyngeal carcinoma (NPC) lacks effective diagnostic and therapeutic strategies, in particular at advanced stages. Here, the authors show that expression of the somatostatin receptor 2 is induced by Epstein-Barr virus in NPC and has a key role in the diagnosis, imaging, targeted therapies and prognosis of NPC.
AB - Nasopharyngeal cancer (NPC), endemic in Southeast Asia, lacks effective diagnostic and therapeutic strategies. Even in high-income countries the 5-year survival rate for stage IV NPC is less than 40%. Here we report high somatostatin receptor 2 (SSTR2) expression in multiple clinical cohorts comprising 402 primary, locally recurrent and metastatic NPCs. We show that SSTR2 expression is induced by the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) via the NF-kappa B pathway. Using cell-based and preclinical rodent models, we demonstrate the therapeutic potential of SSTR2 targeting using a cytotoxic drug conjugate, PEN-221, which is found to be superior to FDA-approved SSTR2-binding cytostatic agents. Furthermore, we reveal significant correlation of SSTR expression with increased rates of survival and report in vivo uptake of the SSTR2-binding Ga-68-DOTA-peptide radioconjugate in PET-CT scanning in a clinical trial of NPC patients (NCT03670342). These findings reveal a key role in EBV-associated NPC for SSTR2 in infection, imaging, targeted therapy and survival. Nasopharyngeal carcinoma (NPC) lacks effective diagnostic and therapeutic strategies, in particular at advanced stages. Here, the authors show that expression of the somatostatin receptor 2 is induced by Epstein-Barr virus in NPC and has a key role in the diagnosis, imaging, targeted therapies and prognosis of NPC.
KW - association
KW - carcinoma
KW - neuroendocrine tumors
KW - NEUROENDOCRINE TUMORS
KW - CARCINOMA
KW - ASSOCIATION
U2 - 10.1038/s41467-020-20308-8
DO - 10.1038/s41467-020-20308-8
M3 - Article
C2 - 33402692
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 117
ER -