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

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.

SSTR2 in Nasopharyngeal Carcinoma: Relationship with Latent EBV Infection and Potential as a Therapeutic Target

“…Ultimately, the aberrant regulation of the NF-κB pathways is significant in NPC tumorigenesis, such as through inducing inflammation, promoting cell survival and proliferation, reprogramming cellular metabolism and activating EBV latent genes including BARTs . As recently shown, LMP1 induces SSTR2 via the NF-κB pathway in NPC ( Figure 4 ), which helps to explain the relevance of SSTR2 in exploring diagnosis, immunohistochemistry, imaging methods and treatment options in NPC [ 5 ].…”

“…We will look at treatment options in further detail later in this review including potential novel treatment options which may be more promising than the currently used octreotide and lanreotide. Recently, our consortium led by Lechner et al performed immunohistochemistry on the largest published series of primary, recurrent, and metastatic NPCs to reveal that SSTR2 expression is found in 81% of primary tumor samples [ 5 ]. There was no significant difference in expression levels between cases and, interestingly, expression was maintained in locally recurrent and metastatic disease, indicating the potential broad clinical utility of SSTR2 in this setting.…”

“…It has long been known that LMP1 mediates NF-κB activation via two effector regions in its carboxy-terminal cytoplasmic domain, as demonstrated by Heun et al in 1995 [ 63 ]. In NPC, LMP1-modulated NK-κB activation was shown to induce SSTR2 expression [ 5 ]. Furthermore, NF-κB signaling may also be activated by EBV-miR-BART13, an EBV micro-RNA which was shown to promote NPC cell growth and metastasis in both in vitro and in vivo studies [ 64 ].…”

“…This superiority is greater still in the case of SSTR2-expressing cells as 68Ga-DOTA-octapeptides were shown to bind SSTR2 100 times more avidly than indium-111 pentetreotide [ 67 ]. SSTR2 therefore shows potential as a diagnostic NPC biomarker when coupled with appropriate imaging techniques as demonstrated by a recent clinical trial published in 2021 as part of a larger study by Lechner et al, which found a significant correlation of SSTR2 expression with in vivo 68-DOTA-peptide uptake in 12 NPC patients [ 5 ]. This built on research by Khor et al conducted in 2015 which demonstrated 68Ga-DOTA-peptide PET/CT as an effective biomarker for newly diagnosed undifferentiated NPC [ 68 ].…”

“…It was shown that EBV infection upregulates the expression of the somatostatin receptor 2 (SSTR2) [ 5 ]. SSTR2 is a G protein-coupled receptor (GPCR), encoded by a gene located on the long arm of chromosome 17.…”