Background: While the clinical use of radiolabeled somatostatin analogs is well established in neuroendocrine tumors, there is growing interest in expanding their application to other somatostatin receptor 2 (SSTR2)-expressing cancers. This study investigates the potential utility of SSTR2-targeted theranostics in hepatocellular carcinoma (HCC). Methods: SSTR2 expression in HCC cell lines and clinical samples was evaluated using qRT-PCR, Western blot analysis, and a public dataset. ⁶⁷Ga-DOTATATE uptake was measured, ¹⁷⁷Lu-DOTATATE cytotoxicity was assessed, and ⁶⁸Ga-DOTATATE tumor targeting was evaluated in HCC animal models and a patient via PET/CT imaging. Results: SSTR2 expression was confirmed in HCC cell lines and clinical samples. Radioligand uptake studies demonstrated SSTR2-mediated ⁶⁷Ga-DOTATATE uptake. ¹⁷⁷Lu-DOTATATE treatment reduced cell proliferation and enhanced the anti-tumor efficacy of the multikinase inhibitor sorafenib. ⁶⁸Ga-DOTATATE PET/CT scans successfully identified tumors in HCC animal models and spinal metastases in a patient with HCC. Conclusion: These findings provide evidence that SSTR2-based theranostics could have significant implications for the detection and treatment of HCC.

Resistance to alkylating chemotherapeutic agents such as temozolomide (TMZ) is a significant challenge in treating tumors with high MGMT expression, including MGMT-positive glioblastoma and neuroendocrine neoplasms. In this study, we investigated the effect of RNA-binding motif protein 39 (RBM39) downregulation on MGMT protein levels, based on prior observations suggesting an association between these two proteins. Pharmacological depletion or siRNA-mediated knockdown of RBM39 led to a marked reduction in MGMT protein levels in MGMT-expressing cancer cells. We further showed that dual targeting of RBM39 (using indisulam) and MGMT (with O6-benzylguanine) synergistically enhanced MGMT depletion. Functionally, combined indisulam and TMZ treatment significantly increased apoptosis and decreased clonogenic growth in neuroendocrine tumor cells. These findings identify MGMT as a downstream target of RBM39 in MGMT-expressing cancer cells and highlight the therapeutic potential of co-targeting RBM39 and MGMT to overcome resistance to alkylating chemotherapy.

(1) Background: Somatostatin receptor 2 (SSTR2), a G protein-coupled receptor, is overexpressed in multiple malignancies, including hepatocellular carcinoma (HCC). While SSTR2 has traditionally been viewed as an inhibitory receptor involved in suppressing hormone secretion and cell proliferation, emerging evidence suggests a more complex role in cancer biology. However, the functional implications of SSTR2 expression in HCC remain poorly understood. This study aimed to systematically investigate the molecular landscape associated with SSTR2 expression in HCC and evaluate its potential as a therapeutic target. (2) Methods: SSTR2 expression patterns across 22 tumor types were assessed using TNMplot, and its expression in HCC was further validated through The Human Protein Atlas. Integrative analysis of transcriptomic profiles, protein expression data, and somatic copy number alterations was performed using data from The Cancer Genome Atlas (TCGA) to stratify HCC patients by SSTR2 expression levels. Gene Ontology (GO) enrichment analysis was conducted via SRplot to uncover biological processes and signaling pathways associated with SSTR2. Kaplan–Meier survival analyses were performed using GEO datasets to determine the prognostic significance of SSTR2 expression. (3) Results: SSTR2 is moderately expressed in the majority of HCC tumors. Elevated SSTR2 expression correlates with significantly poorer overall and disease-specific survival. High SSTR2 levels are associated with activation of oncogenic signaling cascades related to cell proliferation, epithelial-to-mesenchymal transition (EMT), angiogenesis, and metastasis. Additionally, SSTR2 expression is positively correlated with several receptor tyrosine kinases and oncogenes implicated in HCC progression. (4) Conclusions: Our findings suggest that SSTR2 is not merely a passive biomarker but may contribute to HCC pathogenesis through modulation of oncogenic pathways. These data support the rationale for further development of SSTR2-directed therapeutic strategies to inhibit tumor growth and invasion in HCC patients.

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a desmoplastic, immunosuppressive tumor microenvironment enriched in extracellular adenosine. High adenosine levels disrupt anti-tumor immunity by engaging adenosine receptors on T cells, macrophages, and dendritic cells. In this context, strategies to reduce extracellular adenosine signaling within the TME are in focus. Among them, enzymatic degradation of extracellular adenosine levels has emerged as a promising approach to overcome immune suppression and restore anti-tumor immune responses. Methods: Here, we engineered an E. coli strain to express a surface-bound form of a bacterial ADA2 enzyme and used the outer membrane vesicles produced by this strain as nanoparticles carrying the functional enzyme. Our data indicate robust surface expression and enzymatic activity of ADA2 on OMV particles. Results: In a PDAC subcutaneous flank tumor model, intratumoral administration of OMV-ADA2 particles was associated with significantly increased infiltration of CD8⁺ T cells and Granzyme B expression and concomitant decreases in collagen deposition and α-smooth muscle actin (α-SMA) positive stromal cells, suggesting modulation of the desmoplastic stroma. Conclusions: These findings support further investigation of OMV–bADA2 as a potential platform to modulate tumor metabolism and stroma, activate anti-tumor immunity, and serve as a carrier for co-delivery of additional anticancer modalities in PDAC.