SSTR2-targeting therapy in EBV-positive and EBV-negative metastatic nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV) - associated malignancy prevalent in South Asia, and somatostatin receptors (SSTRs), particularly SSTR2, are expressed in NPC and other solid tumors, suggesting a potential therapeutic target. We observed abundant SSTR2 expression in NPC cell lines and patient-derived xenografts (PDXs). In the EBV-negative PDX-Li41 model, treatment with the SSTR2 agonist octreotide (OCT) significantly inhibited xenograft growth and showed additive effects with chemotherapy; transcriptomic and protein analyses revealed heterogeneous regulation of cell-cycle-related genes, upregulation of DNA replication pathways, downregulation of cell-signaling and neurotransmitter-release pathways, and reduced expression of CDK6, NF-κB, E2F1, CDK2, and BIRC5. In contrast, OCT did not suppress tumor growth in the EBV-positive PDX-B13 model, prompting the development of an octreotide-monomethyl auristatin E (OCT-MMAE) peptide-drug conjugate, which demonstrated efficient cellular internalization, a low IC50 (≈ 10^-7 M), and significant inhibition of xenograft growth in both EBV-positive and EBV-negative PDX models. Evaluation of 118 metastatic NPC tumors showed that 91.5% were SSTR2-positive, and high SSTR2 expression was associated with significantly shorter overall survival (P = 0.001768), indicating that SSTR2 is widely expressed, linked to poor prognosis, and represents a promising therapeutic target in NPC.