Virtual Flash Talk & E-Poster Presentation 34th Lorne Cancer Conference 2022

Inhibition of the NPY signalling axis as a novel therapeutic option in Pancreatic Cancer. (#11)

Cecilia Chambers 1 , Peter Schofield 1 , Jessie Zhu 1 , Daniel Reed 1 , Victoria Lee 1 , Kendelle Murphy 1 , Michael Trpceski 1 , Max Nobis 1 , Lea Abdulkhalek 1 , Xanthe Metcalf 1 , Pauline Melenec 1 , Claire Vennin 1 , Sean Warren 1 , Sunny Wu 1 , Lei Zhang 1 , Ronaldo Enriquez 1 , Yan-Chuan Shi 1 , Mark Pinese 1 , Nicola Waddell 2 , Marina Pajic 1 , Owen Sansom 3 , Jennifer Morton 3 , Daniel Christ 1 , David Herrmann 1 , Herbert Herzog 1 , Paul Timpson 1
  1. The Garvan Institute of Medical Research, Sydney, NSW, Australia
  2. QIMR Berghofer Medical Research Institute, Herston
  3. Cancer Research UK Beatson Institute, Glasgow, United Kingdom

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 diagnosis1. 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of Lewis Lung Carcinoma and B16F10 Melanoma showed significant increases in survival and decrease in tumour burden (unpublished). Here we show in single-cell RNA sequencing (scRNA-seq) 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 its 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 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 tumorigenesis2-7.

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, which is the common site of metastasis in human PC patients. Additionally, our results from anchorage-independent growth (AIG) assays that mimic the loss of PC cell attachment to their environment suggest that the reduced metastasis upon NPY inhibition may be due to 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) setting significantly extended survival.

Finally, we have recently stained tissue microarrays (TMAs) from the International Cancer Genome Consortium (ICGC) cohort of 235 PC patients for NPY expression and are currently in the process of scoring those TMAs to assess NPY expression in relation to PC patient outcomes. Future experiments will 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.     

    

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7-30. doi:10.3322/caac.21590
  2. Zhang L, Bijker MS, Herzog H. The neuropeptide y system: Pathophysiological and therapeutic implications in obesity and cancer. Pharmacol Ther. 2011. doi:10.1016/j.pharmthera.2011.03.011
  3. Loh K, Herzog H, Shi YC. Regulation of energy homeostasis by the NPY system. Trends Endocrinol Metab. 2015;26(3):125-135. doi:10.1016/j.tem.2015.01.003
  4. Hansel DE, Eipper BA, Ronnett G V. Neuropeptide Y functions as a neuroproliferative factor. Nature. 2001;410(6831):940-944. doi:10.1038/35073601
  5. Lee EW, Michalkiewicz M, Kitlinska J, et al. Neuropeptide Y induces ischemic angiogenesis and restores function of ischemic skeletal muscles. J Clin Invest. 2003;111(12):1853-1862. doi:10.1172/JCI16929
  6. Dimitrijević M, Stanojević S. The intriguing mission of neuropeptide y in the immune system. Amino Acids. 2013. doi:10.1007/s00726-011-1185-7
  7. Dietrich P, Wormser L, Fritz V, et al. Molecular cross-talk between Y5-receptor and neuropeptide Y drives liver cancer. J Clin Invest. January 2020. doi:10.1172/jci131919