GHRH-R antagonist MIA-602 inhibits human gastric cancer growth by downregulating PAK1-STAT3/NF-κB signaling

Gastric cancer (GC) is a major global health issue, ranking as the fourth most common cancer and the second leading cause of cancer-related death worldwide. The urgent need for more effective treatment strategies is paramount. Previous research has identified the presence of Growth hormone-releasing hormone (GHRH) and its receptor, GHRH-R, in a variety of tumor tissues. This suggests that inhibiting the GHRH-R could be a viable therapeutic strategy. However, the specific role of the GHRH/GHRH-R axis in human gastric cancer remained largely unexplored, creating a critical knowledge gap. This study investigated whether GHRH-R expression correlates with patient outcomes and if targeting this receptor with an antagonist could represent a new therapeutic avenue for this deadly disease.

Researchers first conducted survival analyses on multiple cohorts of gastric cancer patients to correlate tumor GHRH-R expression with prognosis. Next, they performed in vitro experiments using cultured human GC cells to assess the inhibitory effects of MIA-602, a potent GHRH-R antagonist. The study then progressed to in vivo validation using multiple models where human GC cell lines were xenografted into nude mice. The mechanistic investigation focused on identifying the downstream signaling pathways affected by MIA-602 treatment, specifically looking at the PAK1-STAT3/NF-κB inflammatory cascade.

Survival analysis revealed that increased GHRH-R expression in tumor specimens is an independent predictor of poor prognosis and correlates with worse survival in GC patients. In vitro, the GHRH-R antagonist MIA-602 was found to effectively inhibit the growth of cultured gastric cancer cells. This anti-proliferative effect was subsequently confirmed in vivo across multiple xenograft mouse models.

The core mechanism identified was the targeted downregulation of a specific inflammatory signaling pathway. MIA-602 acts on the GHRH-R to suppress the activity of p21-activated kinase 1 (PAK1), which in turn leads to the downregulation of both signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB (NF-κB). This establishes a clear link between GHRH-R activation and a key pro-cancer inflammatory pathway in gastric cancer.