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. Systemic therapies are largely ineffective for inoperable disease, leading to an overall 5-year survival rate of less than 9%. 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 previously identified that Neuropeptide Y (NPY), normally produced by sympathetic neurons and endocrine cells, has a strong cancer-promoting ability in mouse models of Lewis Lung Carcinoma and B16F10 Melanoma.
We found that 16.16% of PC patients from the Australian Pancreatic Cancer Genome Initiative (APGI) exhibit amplification of NPY signalling components. This evidence led us to investigate the role NPY plays in PC using genetic and pharmacological manipulation of the NPY signalling axis. We show that NPY is overexpressed in tumours and metastases from our genetically engineered invasive and metastatic KPC mouse model (which recapitulates the human disease), relative to wildtype pancreas. Interestingly, NPY is upregulated in KPC cancer cells, while its counterpart Y1 receptor is upregulated in the cancer-associated fibroblasts, suggesting a paracrine interaction between cancer and stromal cells using NPY-signalling. Moreover, inhibition of the NPY signalling axis in combination with standard-of-care gemcitabine in vivo significantly reduces PC tumour growth and metastatic burden within the liver.
Experiments to assess the efficacy of NPY targeting in long-term mouse survival studies and in patient-derived models of PC that are able to be stratified based on NPY/NPY receptor expression levels are currently ongoing, which may inform future tailored applications of our findings.