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

Nat Commun. 2021 Jan 5;12(1):117. 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.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Epstein-Barr Virus Infections / drug therapy
  • Epstein-Barr Virus Infections / genetics*
  • Epstein-Barr Virus Infections / mortality
  • Epstein-Barr Virus Infections / virology
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Herpesvirus 4, Human / drug effects
  • Herpesvirus 4, Human / growth & development
  • Herpesvirus 4, Human / pathogenicity
  • Host-Pathogen Interactions / genetics
  • Humans
  • Lymphatic Metastasis
  • Male
  • Mice
  • Mice, Nude
  • Molecular Targeted Therapy
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Nasopharyngeal Carcinoma / drug therapy
  • Nasopharyngeal Carcinoma / genetics*
  • Nasopharyngeal Carcinoma / mortality
  • Nasopharyngeal Carcinoma / virology
  • Nasopharyngeal Neoplasms / drug therapy
  • Nasopharyngeal Neoplasms / genetics*
  • Nasopharyngeal Neoplasms / mortality
  • Nasopharyngeal Neoplasms / virology
  • Neoplasm Recurrence, Local / drug therapy
  • Neoplasm Recurrence, Local / genetics*
  • Neoplasm Recurrence, Local / mortality
  • Neoplasm Recurrence, Local / virology
  • Octreotide / pharmacology
  • Positron Emission Tomography Computed Tomography
  • Receptors, Somatostatin / antagonists & inhibitors
  • Receptors, Somatostatin / genetics*
  • Receptors, Somatostatin / metabolism
  • Signal Transduction
  • Survival Analysis
  • Viral Matrix Proteins / antagonists & inhibitors
  • Viral Matrix Proteins / genetics*
  • Viral Matrix Proteins / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • EBV-associated membrane antigen, Epstein-Barr virus
  • NF-kappa B
  • Receptors, Somatostatin
  • SSTR2 protein, human
  • Viral Matrix Proteins
  • Octreotide

Associated data

  • ClinicalTrials.gov/NCT03670342