Aims: Localised expression of growth hormone (GH) and its receptor (GHR) has been identified in various human malignancies and is associated with poor survival outcomes in certain types of cancer. Despite evidence from published literature, preclinical studies investigating the anticancer efficacy of growth hormone inhibition have been difficult to undertake due to the limited availability of suitable pharmacological tools for in vivo studies. Pegvisomant, the only clinically available GHR antagonist, is difficult to access for research so novel GHR antagonists are needed to investigate the role of GHR signalling in cancer. Here the preclinical efficacy of a novel long-acting GHR antagonist (GHA2) was investigated in melanoma.
Methods: Recombinant GHA2 protein was expressed and purified from E. coli and conjugated with polyethylene glycol (PEGylated) to extend the in vivo circulating half-life. In vitro bioactivity was confirmed using cell-based assays and inhibition of GHR-dependent signal transduction. For tumour growth studies, melanoma xenografts (NZM79) grown in immunodeficient NIH-III mice were treated daily with vehicle or GHA2 (30 mg/kg/day) ± human GH (2 mg/kg/day) for 2 weeks.
Results: In melanoma cell lines, high GHR mRNA expression was observed across a panel of 24 New Zealand metastatic melanoma (NZM) cell lines. 16/24 cell lines were GH responsive (STAT5 phosphorylation) and responded to GHR antagonism. GH promoted cell proliferation in GHR-positive cell lines. In xenograft studies, serum IGF1 decreased by 51% with GHA2 treatment (p<0.001). GHA2 treatment also significantly decreased the growth rate of NZM79 tumours versus vehicle (p<0.05), and reduced tumour expression of the proliferation marker Ki67.
Conclusion: GHA2 effectively antagonised GH signalling in melanoma cell lines and slowed melanoma tumour growth, highlighting its potential as a therapeutic strategy for treating melanoma.