Assessing the diagnostic, prognostic, and therapeutic potential of the somatostatin/cortistatin system in glioblastoma

Glioblastoma remains an incurable tumour (median survival: ~ 15 months) and little clinical progress has been made over the past decades. Therefore, identification of novel biomarkers and therapeutic targets is imperative. Targeting the somatostatin/cortistatin-system is considered a successful avenue for treating different tumour pathologies. Thus, we comprehensively characterized (clinically and molecularly) the expression of the somatostatin/cortistatin-system components [ligands and receptors (SSTRs)] using five cohorts of patients and tested the in-vitro therapeutic response of different SSTR-agonists and somatostatin analogs (SSAs) in primary patient-derived glioblastoma cells. A clear downregulation of the whole somatostatin/cortistatin-system (except for SSTR5) in glioblastoma vs. non-tumour brain samples was demonstrated, with high discriminatory capacity. Moreover, poor overall-survival and critical aggressiveness-parameters (i.e., recurrence, IDH1-wildtype and G-CIMP status, classical and mesenchymal GBM-subtypes, EGFR-amplification) were robustly associated with SSTR1/SSTR2 downregulation. Notably, octreotide, pasireotide, and SSTR1/2/5-agonists treatments significantly reduced cell-proliferation in primary patient-derived GBM-cells. Molecularly, antitumour effects of octreotide/pasireotide were exerted through key signalling-factors related to glioblastoma-aggressiveness (i.e., CDKN1A-B/JAK-STAT/NF-κB/TGF-β-pathways). Altogether, this study demonstrated that somatostatin/cortistatin-system is drastically altered in GBM representing a useful prognostic tool, and that SSTR-modulators might represent a potential therapeutic strategy to treat specific subsets of patients with GBM.