Publications

The following peer-reviewed publications published by APIM Therapeutics or APIM's CSO and NTNU Professor, Marit Otterlei, provide more info on the PCNA, the APIM-motif and the mechanism of action of ATX-101 in cancer.

  1. Søgaard CK and Otterlei M, 2024. Targeting proliferating cell nuclear antigen (PCNA) for cancer therapy. Advances in Pharmacology, 2024

    This review publication focuses on stress-related roles of proliferating cell nuclear antigen (PCNA), the drug target of ATX-101, and describes how targeting these PCNA roles can be exploited to develop novel cancer therapy approaches.

  2. Lemech CR et al, 2022. ATX-101, a cell-penetrating protein targeting PCNA, can be safely administered as intravenous infusion in patients and shows clinical activity in a Phase 1 study. Oncogene, 2023 Feb;42(7):541-544.

    This publication presents the clinical results obtained with ATX-101 in a phase 1 study conducted in patients with advanced solid tumors. Overall, ATX-101 showed a favorable safety profile supporting that vital cellular functions are not compromised in healthy cells. Furthermore, promising disease stabilization was observed in patients with advanced, progressive tumors lacking standard treatment options. These data support further clinical development of the compound.

  3. Røst LM et al, 2022. PCNA regulates primary metabolism by scaffolding metabolic enzymes. Oncogene, 2023 Feb;42(8):613-624.

    This publication demonstrates that PCNA acts as a scaffold for metabolic enzymes thereby acting as a direct regulator of primary metabolism and cellular signaling. These data corroborate the notion that targeting PCNA and its regulatory roles during cellular stress may be highly relevant for cancer treatment.

  4. Gravina GL et al, 2022. ATX-101, a peptide targeting PCNA, has antitumor efficacy alone or in combination with radiotherapy in murine models of human glioblastoma. Cancers (Basel). 2022 Jan 7;14(2):289.

    This publication shows that ATX-101 has anticancer activity as a single agent in vitro and in vivo. Furthermore, ATX-101 potentiated the effect of Radiotherapy in both subcutaneous and intracranial xenograft tumor models. ATX-101 affected key oncogenic signaling pathways and increased DNA damage and apoptosis when combined with RT. The results of these studies promote future clinical development of ATX-101 in this indication.

  5. Søgaard CK et al, 2019. Targeting the non-canonical roles of PCNA modifies and increases the response to targeted anti-cancer therapy. Oncotarget. 2019 Dec 31;10(68):7185-7197.

    This publication focuses on non-canonical cytosolic roles of PCNA and their targeting via ATX-101; this results in an increase of anti-cancer activity of EGFR/HER2/VEGFR inhibitors in vitro and in vivo. Specifically, the combination treatment results in reduced tumor load and increases the survival compared to either single agent treatments. Moreover, it affects multiple cellular signaling responses not seen by EGFR/HER2/VEGFR inhibition alone. Finally, changes are observed in pathways determining protein degradation, ER-stress, apoptosis and autophagy. These results suggest that targeting the non-canonical roles of PCNA in cellular signaling via ATX-101 has the potential to improve the activity of targeted therapies.

  6. Ræder S et al, 2018. APIM-mediated REV3L–PCNA Interaction important for error free TLS over UV-Induced DNA lesions in human cells. Int J Mol Sci. 2018 Dec 28;20(1).

    This publication validates the APIM motif in the catalytic subunit of the essential mammalian TLS polymerase POLζ, REV3L. ATX-101 reduces the mutation frequencies and changes the mutation spectra in several cell lines, suggesting that efficient TLS requires coordination mediated by interactions with PCNA. This has implication on the mutagenicity potential of multiple treatments in the presence of ATX-101.

  7. Søgaard CK et al, 2018b. “Two hits - one stone”; increased efficacy of cisplatin-based therapies by targeting PCNA’s role in both DNA repair and cellular signaling. Oncotarget, 2018, Vol. 9, (No. 65), pp: 32448-32465

    This publication presents data obtained with ATX-101/cisplatin combinations in in vitro and in vivo models of Muscle Invasive Bladder Cancer (MIBC). Moreover, it presents results from gene expression, proteome/kinome and metabolome studies in MIBC cell lines.

  8. Olaisen C et al, The role of PCNA as a scaffold protein in cellular signaling is functionally conserved between yeast and humans. FEBS Open Bio, 2018, May 31;8(7):1135-1145

    This publication shows that interactions of APIM‐containing signaling proteins and PCNA during the DNA damage response are evolutionary conserved between yeast and mammals and that PCNA has a role in cellular signaling also in yeast.

  9. Søgaard CK et al, 2018a. APIM-peptide targeting PCNA improves the efficacy of docetaxel treatment in the TRAMP mouse model of prostate cancer. Oncotarget. 2018 Jan 27;9(14):11752-11766

    This publication shows that ATX-101 improves docetaxel treatment efficacy in prostate cancer by affecting multiple signaling and apoptotic pathways.

  10. Olaisen C et al, 2015. PCNA-interacting peptides reduce Akt phosphorylation and TLP-mediated cytokine secretion suggesting a role of PCNA in cellular signaling. Cell Signal. 2015 Jul;27(7):1478-87

    Publication showing that PCNA has a platform role in cytosol affecting cellular signaling and inflammatory responses. These effects suggest a role of PCNA in inflammatory disorders as well as cancer inflammation.

  11. Gederaas OA et al, 2014. Increased anti-cancer efficacy of intravesical mitomycin C therapy when combined with a PCNA targeting peptide. Translational Oncology, Volume 7, Issue 6, 812–823, Dec. 2014

    Publication describing validation and in vivo proof-of-efficacy results of ATX-101 in bladder cancer cells and in two orthotopic rat bladder models in combination with Mitomycin-C and bleomycin.

  12. Baglo Y et al, 2014. Enhanced efficacy of bleomycin in bladder cancer cells by photochemical internalization. Biomed Res Int. 2014, 2014:921296

    Publication addressing the ability of ATX-101 to enhance the action of bleomycin in bladder cancer cell lines.

  13. Müller R et al, 2013. Targeting proliferating cell nuclear antigen and its protein interactions induces apoptosis in multiple myeloma cells. PLoS One. 2013 Jul 31;8(7)

    Publication describing ATX-101, its capacity to target PCNA and key in vitro and mechanism of action results in combination with several chemotherapeutic treatments. Describes validation of ATX-101 in multiple myeloma ex vivo (patient cancer cells) and in vivo (mouse myeloma xenografts).

  14. Gilljam KM et al, 2012. Nucleotide excision repair is associated with the replisome and its efficiency depends on a direct interaction between XPA and PCNA. PLoS One. 2012;7(11):e49199

    Publication showing that XPA, a protein in the NER pathway, bears a functional APIM; XPA’s function in UV induced damage is dependent on an intact APIM sequence.

  15. Gilljam KM et al, 2009. Identification of a novel, widespread, and functionally important PCNA-binding motif.  J Cell Biol, 2009, 186: pp645-654

    Pivotal NTNU publication describing APIM; reported results link APIM with the potentiation of the activity of several chemotherapeutic treatments in cancer cells.