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 worldwide, with > 90% of patient deaths occurring within 1 year of diagnosis. 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) 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of Lewis Lung Carcinoma and B16F10 Melanoma showed significant increases in survival and decrease in tumour burden (unpublished). Here we show in single-cell RNA sequencing datasets of tumours from the genetically engineered KPC mouse model of PC (Pdx1-Cre; KrasG12D/+; p53R172H/+) that NPY is highly expressed in epithelial populations while it’s corresponding receptor Y1 is predominantly expressed in CAFs. We confirmed these results using q-RT-PCR in established KPC cancer cells and CAF lines from our lab. Moreover, RNAscope and IHC showed that NPY expression was significantly upregulated in KPC tumours compared to wild-type normal pancreas. Additionally, 16.16% of PC patients from the Australian Pancreatic Cancer Genome Initiative (APGI) show an amplification of NPY signalling components. This evidence alongside NPY’s known role in numerous tumour promoting pathways including energy homeostasis, cell proliferation, tissue fibrosis, angiogenesis, and neuromodulation of the immune system lead us to investigate further the role it plays in PC tumorigenesis.
Using pharmacological approaches to inhibit the NPY signalling axis, including a novel NPY-blocking antibody 5E12 created at the Garvan Institute (of which we also have a humanised version), we show that NPY inhibition in a subcutaneous xenograft model significantly reduces PC tumour growth in combination with standard-of-care gemcitabine. Furthermore, in an intrasplenic model of PC metastasis, we show that combination of 5E12 and gemcitabine significantly reduces metastatic burden within the liver. Additionally, our results from anchorage-independent growth (AIG) assays that mimic the loss of PC cell attachment to their environment suggest that this reduced metastasis may be exposing PC cell vulnerability to chemotherapy while in transit to secondary sites. Importantly, NPY inhibition with our monoclonal antibody in a long-term orthotopic (intra-pancreatic) significantly extended survival.
Future experiments aim to stratify PC patients based on NPY expression levels for treatment of patient-derived xenografts (PDXs) with our therapeutic antibody in combination with standard-of-care chemotherapy, thereby providing clinical relevance and feasibility for this project.