OR05-04 Growth Hormone Receptor Antagonism Markedly Improves Therapeutic Response In Mouse Models Of Melanoma, Liver Cancer, Pancreatic Cancer And Cholangiocarcinoma

Abstract

Abstract Disclosure: R. Basu: None. P. Kulkarni: None. S. Duran Ortiz: None. E. Davis: None. J.J. Kopchick: None. A major hurdle in tackling cancer, the second biggest cause of human mortality, is resistance to therapy. Human growth hormone (GH) mediated activation of the growth hormone receptor (GHR) promotes the initiation and invasive progression of several types of human cancers, known since 1950. Recently, through a series of mechanistic studies using in vitro models and in silico analyses of human cancer patient databases, we have identified a covert role of GH in promoting cancer drug resistance via direct upregulation of: (i) the expression of ATP-binding cassette containing multi-drug transporters (ABC transporters) leading to increased drug efflux, (ii) the epithelial-to-mesenchymal transition (EMT) associated gene expression program, and (iii) the mediators of fibrosis and extracellular matrix remodeling. Additionally, based on the known effects of GH and robust expression of GHR in multiple cell types that constitute the tumor microenvironment, autocrine / paracrine GH putatively exerts potent tumor supportive actions. Therefore, we hypothesized that combining GHR antagonist to chemotherapy can markedly improve therapeutic outcome in human cancers. Melanoma and liver cancer jointly and annually constitute >150,000 patients and >60,000 deaths in the US, much due to resistance to therapy. We used a syngeneic murine model of both cancers using C57BL6 mice transgenic for a GHR antagonist (GHA mice) compared against wild-type (WT) counterparts implanted with either B16F10 melanoma or Hepa-1-6 hepatoma cells. GHA expression drastically sensitized melanoma tumors to cisplatin treatment and hepatoma tumors to sorafenib treatment. Additionally, the five-year survival rates of pancreatic cancer and cholangiocarcinoma are a dismal 10% in 2022, indicating an urgent need for new therapeutic approaches for both of these devastating diseases. For this, we used Nude mice for human pancreatic cancer xenografts treated +/- GHA (Pegvisomant and another in development at our laboratory) combined with gemcitabine. Combination of GHA markedly sensitized pancreatic cancer xenografts to gemcitabine in Nude mice, leading to ∼40% of mice being tumor-free at the end of study. GHA similarly also sensitized human cholangiocarcinoma xenografts in Nude mice to gemcitabine-cisplatin therapy. In all cases, GHA led to a marked reduction in gene expression of multidrug efflux transporters, EMT markers, and fibrosis mediators. Collectively, our data provides strong pre-clinical validation for treatment regimens combining GHR antagonist and chemotherapy leading to highly efficacious tumor clearance. Presentation: Thursday, June 15, 2023