Combination of growth hormone receptor antagonist and radiation reduces tumour growth in a lung cancer xenograft model

Lung cancer is the primary cause of cancer-related deaths worldwide. A substantial proportion of patients will undergo radiotherapy during treatment. The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis has been implicated in cancer progression and resistance to radiation therapy. Elevated GH receptor (GHR) mRNA expression is observed in tumour tissue from non-smoking female patients with non-small cell lung cancer (NSCLC) and a genetic variant in the GHR is associated with increased lung cancer risk. Here, we evaluate the efficacy of a GHR antagonist (GHA2) in combination with radiation therapy in a NSCLC xenograft model. NCI-H460 xenografts grown in immunodeficient NIH-III mice were treated with PEGylated GHA2 (GHA2-PEG) (30 mg/kg/day) ± fractionated gamma radiation (10 × 2.5 Gy over 5 days). IGF-1 concentrations were reduced by 56-59% in GHA2-PEG-treated groups compared to vehicle-treated controls. Treatment with GHA2-PEG significantly increased the median time tumours took to reach 4× the pre-radiation treatment volume when compared to radiation alone (28 versus 23 days; P < 0.05). Immunohistochemical analysis demonstrated that treatment with GHA2-PEG decreased the area of CD31 labelling in irradiated tumours, suggesting an anti-vascular effect, but this was not observed in non-irradiated tumours. Moreover, administering GHA2-PEG significantly reduced the area of CD11b labelling in non-irradiated tumours, and reduced pimonidazole staining in irradiated tumours, indicating that GHR antagonism reduced tumour angiogenesis and hypoxic regions. Our results suggest that GHA2-PEG treatment sensitises NSCLC cell NCI-H460 to radiation and may improve the response of GH- and/or IGF1-responsive lung tumours to radiotherapy.