APIM-peptide targeting PCNA improves the efficacy of docetaxel treatment in the TRAMP mouse model of prostate cancer

// Caroline K. Søgaard 1, 7 , Siver A. Moestue 2, 3, 4 , Morten B. Rye 1, 7 , Jana Kim 2, 5 , Anala Nepal 1 , Nina-Beate Liabakk 1 , Siri Bachke 1 , Tone F. Bathen 2, 5 , Marit Otterlei 1, 6, 7 and Deborah K. Hill 2, 5 1 Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway 2 Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway 3 Department of Laboratory Medicine, Women’s and Children’s Health, Norwegian University of Science and Technology (NTNU), Trondheim, Norway 4 Department of Pharmacy, Faculty of Health Sciences, Nord University, Namsos, Norway 5 Department of Radiology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway 6 APIM Therapeutics A/S, Trondheim, Norway 7 Clinic of Surgery, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway Correspondence to: Marit Otterlei, email: marit.otterlei@ntnu.no Deborah K. Hill, email: deborah.hill@ntnu.no Keywords: magnetic resonance imaging; gene expression; apoptosis; MAPK; PI3K/AKT Received: June 07, 2017      Accepted: November 06, 2017      Published: January 27, 2018 ABSTRACT Docetaxel is the chemotherapeutic choice for metastatic hormone-refractory prostate cancer, however, it only marginally improves the survival rate. The purpose of the present study was to examine if a peptide targeting the cellular scaffold protein PCNA could improve docetaxel’s efficacy. We found that docetaxel given in combination with a cell penetrating peptide containing the AlkB homolog 2 PCNA interacting motif (APIM-peptide), reduced the prostate volume and limited prostate cancer regrowth in vivo in the immunocompetent transgenic adenocarcinoma model of prostate cancer (TRAMP). In accordance with this, we found that the APIM-peptide enhanced the efficacy of docetaxel in vitro . Gene expression analysis on prostate cancer cell lines indicated that the combination of docetaxel and APIM-peptide alters expression of genes involved in cellular signaling, apoptosis, and prostate cancer development. These changes were not detected in single agent treated cells. Our results suggest that targeting PCNA and thereby affecting multiple cellular pathways simultaneously has the potential to improve docetaxel therapy of advanced prostate cancer.