Reduced Tumor Load And Metastasis In Vivo By Targeting A Metalloprotease-Disintegrin, Adam8, In Highly Invasive Adenocarcinomas

ADAM proteases (A Disintegrin And Metalloprotease Domain) are multi domain proteases with functions in tumor cell growth, cell adhesion and ECM remodeling. High expression levels of ADAM8 are correlated with bad patient prognosis in brain, lung, and pancreatic cancer. The objective of this study was to validate ADAM8 as drug target in adenocarcinomas. In pancreatic tumor cells Panc1, ADAM8 overexpression (Panc1/A8) leads to increased cell migration and cleavage of fibronectin and collagen I and IV, causing enhanced invasion into the ECM via ADAM8. In Panc1/A8 cells, ADAM8 interacts with β1 integrin, activating ERK, Akt and p38 pathways. Panc1/A8 cells were grafted orthotopically into pancreas of nude mice. Larger tumors were found from Panc1/A8 cells compared to control cells. More importantly, higher metastatic load from these cells in liver and spleen was observed. As therapy approach, we designed a cyclic peptide (“cycP1”) mimicking the integrin binding loop of ADAM8. CycP1 impedes ADAM8‐β1 integrin interactions causing reduced intracellular signaling. In vivo , cycP1 is very potent in reducing tumor load and formation of metastases compared to untreated mice. Our results suggest that inhibition of ADAM8 in highly invasive adenocarcinomas is feasible for therapeutic intervention and provides a solid basis for further preclinical drug development. Supported by Cancer Research UK.