Due to surgically unresectable, locally advanced or metastatic disease being present at the time of clinical diagnosis, pancreatic cancer (PC) is one of the most lethal forms of human cancer, with > 90% of patient deaths occurring within 1 year of diagnosis [1]. Systemic therapies are largely ineffective for inoperable disease, leading to an overall 5-year survival rate of less than 8% [2]. Consequently, the development of more effective strategies to overcome these limitations and efficiently treat PC is required.
Exciting new research from the Garvan Institute has identified that Neuropeptide Y (NPY), normally produced by sympathetic neurons and endocrine cells, has a strong cancer-promoting ability and inhibition of the NPY signalling axis in mouse models of Lewis Lung Carcinoma and B16F10 Melanoma showed significant increase in survival and decrease in tumour burden (unpublished). Tumours from our invasive PC mouse models exhibit increased NPY expression and 16.16% of PC patients from the Australian Pancreatic Cancer Genome Initiative (APGI) show an amplification of NPY signalling components. This evidence lead us to investigate the role NPY plays in PC.
Here, we show in our well-established mouse model of PC (KPC), which is driven by mutations in Kras and p53, that are also commonly mutated in human PC that:
(i) NPY RNA and protein expression is up-regulated in primary tumours and metastases compared to wildtype pancreas
(ii) Inhibition of NPY signalling in vitro with a small molecule inhibitor and a novel blocking antibody (for which we also have a humanised version available) reduces PC cell migration, cell streaming and cell cycle progression.
Experiments to block NPY in our in vivo mouse models and in patient-derived models of PC are currently ongoing, which may inform future applications.