Poster Presentation 29th Lorne Cancer Conference 2017

Local inhibition of IGF-signaling in cancer by blockade of PAPPA (#122)

Marissa Blume 1 , Prashanth Prithviraj 1 , Matthew Anaka 1 , Sonja J McKeown 2 , Micheal Permezel 3 , Marzena Walkiewicz 1 , Jonathan Cebon 1 , Aparna Jayachandran 1 , Andreas Behren 1
  1. Olivia Newton-John Cancer Research Center, Heidelberg, VICTORIA, Australia
  2. Department of Anatomy and Neuroscience, University of Melbourne, Melbourne
  3. Mercy Hospital for Women, Melbourne

Multiple studies have linked dysregulated IGF-signalling to cancer and acquired therapy resistance. Clinical trials have aimed at improving patient outcomes by targeting IGFR1. Anti-IGFR1 antibodies act globally and cross-react with the structurally similar insulin receptor. IGF signalling is regulated in part by the Pregnancy-Associated Plasma Protein-A (PAPPA), a metalloproteinase that associates with cell surface heparan sulfate proteoglycans at the site of its expression. PAPPA cleaves the circulating inactive complex formed by IGF and the IGF binding protein (IGFBP)-4, releasing IGF and therefore activating IGFR-signalling. We have demonstrated that PAPPA is widely expressed in metastatic melanoma cells and influences their invasion, migration and progression. Moreover, in melanomas with acquired resistance against BRAF inhibitor - which are standard of care for patients with melanomas harbouring a V600 BRAF mutation - we have demonstrated via phoshoproteomics a connection to increased phosphorylation of IGF-signalling pathway members. Further, we found up regulation of PAPPA expression after establishing BRAFi resistance in cell lines through long-term culture in BRAFi. To improve the outcomes of BRAFi resistant patients PAPPA will be pursued as a possible target for co-treatment. Interestingly, PAPPA is expressed in high levels by the placenta during pregnancy as well and an increased ratio of observed-to-expected rates of melanoma has been observed in pregnant women. Pregnant women are more prone to dismal outcomes and an increased risk of recurrence from clinical experience. The elevated PAPPA expression and therefore high IGF bioavailability may explain these observations.