Background and activities
- 2010- CSO, APIM Therapeutics, Trondheim, Norway (part time)
- 2003- Professor, Faculty of Medicine and Health Sciences, Department of Clinical and Molecular medicine (IKOM), Norwegian University of Science and Technology (NTNU), Trondheim, Norway (main position).
- Visiting scientist at Centre de Rescherche en Cancerologies de Marseille (CRCM), France (spring) and Department of Biology, University of Copenhagen, Denmark (fall), 2019.
- Visiting scientist at Laboratory of Molecular Gerontology, National Institute on Aging, National Institute of Health, Baltimore, USA, 2003-2003.
- Researcher/group leader, Department of Cancer Research, NTNU, after receiving a carrier grant from RCN on the project “Replication associated DNA repair”, 2002-2006.
- Associated professor II, UNIGEN, Center for Molecular biology and Dept. of Cancer Research, University of Trondheim, UNIT (now NTNU), 1988-2002.
- Postdoctoral fellow in DNA repair at UNIGEN, Center for Molecular biology, UNIT (now NTNU), 1994-2001.
- PhD (Dr.ing) in innate immunity at Department of Biotechnology in collaborations with the Department of Cancer Research, The Norwegian Institute of Technology, NTH/UNIT (now NTNU), 1994.
- MSc (Siv.ing) from the Department of Biotechnology, NTH (now NTNU), 1988.
Proteins in the DNA sliding clamp family are structurally conserved essential proteins in all three kingdoms of life. Their role in DNA replication and repair is well known, but the recently discovered roles of the eukaryote DNA sliding clamp PCNA in regulation of cellular signaling, cellular metabolism and apoptosis indicate that this family of proteins has additional functions of importance for cellular stress responses. This highlights the clamp family as promising drug targets.
Based on the scientific discovery of the novel PCNA interaction motif, APIM, Otterlei founded the NTNU spin-off company APIM Therapeutics in 2009, and has since then been in charge of the development of a peptide drug containing the APIM sequence for use in cancer therapy as a part time CSO in APIM Therapeutics (https://www.apimtherapeutics.com/). Clinical trial (phase I) started fall 2018 and will be closed within the summer/early fall of 2020. The drug is well tolerated, and further Phase II studies are planned.
Central studies for understanding of the processes regulated by APIM-PCNA interactions and therefore important for understanding the mode of action of the APIM-peptide drug are:
- Basic research exploring the roles of the APIM – PCNA interactions in the regulation of DNA repair (Gilljam et al., 2009 (PMID 19736315) and 2012 (PMID 23152873)), DNA damage tolerance (Ræder et al., 2018 (PMID 30597836) and Seelinger and Otterlei, 2019 (PMID 31973093)) and cellular stress signaling (Olaisen et al, 2015 (PMID 25797046) and 2018 (PMID 29988559)
- In vivo anti-cancer effects (animal models) and cellular effects of targeting PCNA with peptides containing APIM (Gederaas et al., 2014 (PMID 25500092), Søgaard et al., 2018 (PMID 29545934) and (PMID 30197755), Søgaard et al., 2019 (PMID 31921382), Røst et al., 2020 (doi.org/10.1101/2020.04.29.067512).
During studies of the peptide as an anti-cancer drug, an infection in one of the cell cultures lead to the discovery of the peptide’s antibacterial activity. This activity is recently shown to be linked its interaction with the beta-clamp (Nedal et al. 2020 (PMID 32347931).
The research group’s current focus is to further explore peptides targeting the bacterial DNA sliding clamp for anti-bacterial activities.
- Select a clinical indication for further development
- Explore the beta-clamp’s role outside DNA replication, i.e. elucidate the involvement in regulation of cellular signaling and metabolism
- Explore the interaction between the APIM-peptide and its target.
Increase the understanding of the complex roles of the DNA clamp in prokaryotes is important for development of drugs targeting the beta-clamp.
The project “Targeting AMR by inhibition of bacterial stress responses”, TAMiR, (https://www.ntnu.edu/ikom/tamir#/view/about) is one out of four AMR related projects in Norway funded by the Trond Mohn Foundation (TMS) (see: https://mohnfoundation.no/amr-prosjekter/).
Scientific, academic and artistic work
A selection of recent journal publications, artistic productions, books, including book and report excerpts. See all publications in the database
- (2021) Novel Peptides Targeting the β-Clamp Rapidly Kill Planktonic and Biofilm Staphylococcus epidermidis Both in vitro and in vivo. Frontiers in Microbiology.
- (2021) Nucleoside Analogues Are Potent Inducers of Pol V-mediated Mutagenesis. Biomolecules. vol. 11 (6).
- (2020) Peptides containing the PCNA interacting motif APIM bind to the beta-clamp and inhibit bacterial growth and mutagenesis. Nucleic Acids Research (NAR). vol. 48 (10).
- (2020) The human RAD5 homologs, HLTF and SHPRH, have separate functions in DNA damage tolerance dependent on the DNA lesion type. Biomolecules. vol. 10 (3).
- (2020) Helicase-Like Transcription Factor HLTF and E3 Ubiquitin Ligase SHPRH Confer DNA Damage Tolerance through Direct Interactions with Proliferating Cell Nuclear Antigen (PCNA). International Journal of Molecular Sciences. vol. 21 (693).
- (2019) Alkyladenine DNA glycosylase associates with transcription elongation to coordinate DNA repair with gene expression. Nature Communications. vol. 10 (1).
- (2019) The PCNA interaction motifs revisited: thinking outside the PIP-box. Cellular and Molecular Life Sciences (CMLS). vol. 76 (24).
- (2019) 5-hydroxymethylcytosine marks mammalian origins acting as a barrier to replication. Scientific Reports. vol. 9.
- (2019) Targeting the non-canonical roles of PCNA modifies and increases the response to targeted anti-cancer therapy. OncoTarget. vol. 10 (68).
- (2018) The role of PCNA as a scaffold protein in cellular signaling is functionally conserved between yeast and humans. FEBS Open Bio. vol. 8 (7).
- (2018) Anti-Cancer Potential of Homemade Fresh Garlic Extract Is Related to Increased Endoplasmic Reticulum Stress. Nutrients. vol. 10 (4).
- (2018) APIM-mediated REV3L?PCNA interaction important for error free TLS over UV-induced DNA lesions in human cells. International Journal of Molecular Sciences. vol. 20 (1).
- (2018) APIM-peptide targeting PCNA improves the efficacy of docetaxel treatment in the TRAMP mouse model of prostate cancer. OncoTarget. vol. 9 (14).
- (2018) "Two hits - one stone" increased efficacy of cisplatin-based therapies by targeting PCNA's role in both DNA repair and cellular signaling. OncoTarget. vol. 9 (65).
- (2017) Monitoring of the spatial and temporal dynamics of BER/SSBR pathway proteins, including MYH, UNG2, MPG, NTH1 and NEIL1-3, during DNA replication. Nucleic Acids Research (NAR). vol. 45 (14).
- (2017) Changes in cellular signaling proteins in extracts from A549, H460, and U2OS cells treated with cisplatin or docetaxel. Data in Brief. vol. 12.
- (2017) On-column trypsinization allows for re-use of matrix in modified multiplexed inhibitor beads assay. Analytical Biochemistry. vol. 523.
- (2017) P38 MAPK signaling and phosphorylations in the BRCT1 domain regulate XRCC1 recruitment to sites of DNA damage. Scientific Reports. vol. 7 (1).
- (2016) A-kinase anchoring protein AKAP95 is a novel regulator of ribosomal RNA synthesis. The FEBS Journal. vol. 283 (4).
- (2015) PCNA-interacting peptides reduce Akt phophorylation and TLR-mediated cytokine secretion suggesting a role of PCNA in cellular signaling. Cellular Signalling. vol. 27 (7).