Somatostatin receptor 2 expression in nasopharyngeal cancer is induced by Epstein Barr virus infection: impact on prognosis, imaging and therapy

Matt Lechner ,Liam Masterson ,Kwok Wai Lo ,Renske Fles ,Ka‐Fai To ,Grace Tin‐Yun Chung ,Yim Ling Yip ,Wan He ,Rajeev Gupta ,Guido Wollmann ,Quynh‐Thu Le ,Reshma Nibhani ,Martin Philpott ,Susanne Sprung ,Jacklyn Liu ,Liesa-Marie Schreiber ,Shuting Han ,József Dudás ,Melvin L.k Chua ,Tim R Fenton ,Amit Jain ,David Howard ,Nischalan Pillay ,Bart Vanhaesebroeck ,Sai Wah Tsao ,Kelvin Siu Hoong Loke ,Wen Long Nei ,Feng Wu ,Christodoulos P Pipinikas ,I Indrawati ,Annika Krapp ,Robert B West ,Joshua K Tay ,Amrita Jay ,Christopher G Bell ,Daniele Morelli ,G Royle ,Liam Sutton ,Cillian T Forde ,Peter H Hwang ,Christopher D Steele ,Bing Teng ,Wayne Pearce ,Henri Jacques Delecluse ,Herbert Riechelmann ,Udo Oppermann ,Volker Hans Schartinger ,Martin Förster ,Mohd Afiq Mohd Slim ,Yuk Yu Chan ,Christina Thirlwell ,Hongtao Jin ,P Busson ,Rui‐Hua Xu ,Simon Wan ,Graham Wells ,Teresa Marafioti ,Zhiqiang Cheng ,Susanne Delecluse ,Camelia Herdini ,Johannes Haybaeck ,Stefan M Willems ,Chi Man Tsang ,Júlia Koller ,Haitao Wang ,Joe Yeong ,Christian Uprimny ,Kerry Chester ,Sagung Rai Indrasari ,Tim Meyer ,Marc Lucas Ooft ,Valerie J Lund

doi:10.1038/s41467-020-20308-8

Abstract

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-κB 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 68Ga-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.

Highlights

Nasopharyngeal cancer (NPC), endemic in Southeast Asia, lacks effective diagnostic and therapeutic strategies
We show that somatostatin receptor 2 (SSTR2) expression is induced by the Epstein–Barr virus (EBV) latent membrane protein 1 (LMP1) via the NF-κB pathway
By integrating the mechanisms of SSTR2 expression, preclinical studies and imaging findings, we propose an updated model of NPC carcinogenesis in parallel with potential diagnostic, prognostic, monitoring, and therapeutic strategies (Fig. 4e; related literature can be found in Refs. 25–28)

Summary

Introduction

Nasopharyngeal cancer (NPC), endemic in Southeast Asia, lacks effective diagnostic and therapeutic strategies. 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-κB pathway. We reveal significant correlation of SSTR expression with increased rates of survival and report in vivo uptake of the SSTR2-binding 68Ga-DOTA-peptide radioconjugate in PET-CT scanning in a clinical trial of NPC patients (NCT03670342). These findings reveal a key role in EBVassociated NPC for SSTR2 in infection, imaging, targeted therapy and survival.

Methods

Findings

Conclusion