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

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.


Statistics
For all statistical analyses, confirm that the following items are present in the figure legend, table legend, main text, or Methods section.
n/a Confirmed The exact sample size (n) for each experimental group/condition, given as a discrete number and unit of measurement A statement on whether measurements were taken from distinct samples or whether the same sample was measured repeatedly The statistical test(s) used AND whether they are one-or two-sided Only common tests should be described solely by name; describe more complex techniques in the Methods section.
A description of all covariates tested A description of any assumptions or corrections, such as tests of normality and adjustment for multiple comparisons A full description of the statistical parameters including central tendency (e.g. means) or other basic estimates (e.g. regression coefficient) AND variation (e.g. standard deviation) or associated estimates of uncertainty (e.g. confidence intervals) For null hypothesis testing, the test statistic (e.g. F, t, r) with confidence intervals, effect sizes, degrees of freedom and P value noted Give P values as exact values whenever suitable.

For Bayesian analysis, information on the choice of priors and Markov chain Monte Carlo settings
For hierarchical and complex designs, identification of the appropriate level for tests and full reporting of outcomes Estimates of effect sizes (e.g. Cohen's d, Pearson's r), indicating how they were calculated Our web collection on statistics for biologists contains articles on many of the points above.

Software and code
Policy information about availability of computer code Data collection

Data analysis
For manuscripts utilizing custom algorithms or software that are central to the research but not yet described in published literature, software must be made available to editors/reviewers. We strongly encourage code deposition in a community repository (e.g. GitHub). See the Nature Research guidelines for submitting code & software for further information.

Data
Policy information about availability of data All manuscripts must include a data availability statement. This statement should provide the following information, where applicable:    diffuse type lymphoma (0/3), transitional cell carcinoma and leiomyosarcoma in smooth muscle (0/3), osteosarcoma (0/1), and spindle cell rhabdomyosarcoma (0/1). 2.Immunoreactivity of CONFIRM anti-Synaptophysin (SP11) was also evaluated by testing a variety of formalin fixed, parrafin embedded neoplastic neuroendocrine tissues. For neuroendocrine tissue, 288 samples were stained and evaluated for positivity. 129/288 neuroendocrine cases demonstrated positive staining with the antibody. 3.Interrun reproducibility was determined by staining 5 replicate slides containing the same 3 tissues from duplicate sample types across a dynamic staining range (high expressing tumor, low expressing tumor and normal tissue) over 5 days on a BenchMark XT instrument. 148 of 150 tissues tested scored equivalently. 4.Intra-run reproducibility was determined by staining 14 replicate slides containing the same 3 tissues from duplicate sample types across a dynamic staining range on a BenchMark XT instrument. 83 of 84 tissues tested scored equivalently. 5.Intra-platform reproducibility was determined by staining 5 replicate slides containing the same 3 tissues from duplicate sample types across a dynamic staining range over 3 BenchMark XT instruments. 89 of 90 tissues tested scored equivalently.