University of Oulu

Shoshy A. Brinch, Enya Amundsen-Isaksen, Sandra Espada, Clara Hammarström, Aleksandra Aizenshtadt, Petter A. Olsen, Lone Holmen, Merete Høyem, Hanne Scholz, Gunnveig Grødeland, Sven T. Sowa, Albert Galera-Prat, Lari Lehtiö, Ilonka A.T.M. Meerts, Ruben G.G. Leenders, Anita Wegert, Stefan Krauss, Jo Waaler; The Tankyrase Inhibitor OM-153 Demonstrates Antitumor Efficacy and a Therapeutic Window in Mouse Models. Cancer Research Communications 8 April 2022; 2 (4): 233–245. https://doi.org/10.1158/2767-9764.CRC-22-0027

The tankyrase inhibitor OM-153 demonstrates updates antitumor efficacy and a therapeutic window in mouse models

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Author: Brinch, Shoshy A.1,2; Amundsen-Isaksen, Enya1,2; Espada, Sandra1,2;
Organizations: 1Department of Immunology and Transfusion Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
2Hybrid Technology Hub–Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
3Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
4Department of Transplant Medicine and Institute for Surgical Research, Oslo University Hospital, Rikshospitalet, Oslo, Norway
5Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
6Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland
7Symeres, Nijmegen, the Netherlands
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 4.3 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2022112867332
Language: English
Published: American Association for Cancer Research, 2022
Publish Date: 2022-11-28
Description:

Abstract

The catalytic enzymes tankyrase 1 and 2 (TNKS1/2) alter protein turnover by poly-ADP-ribosylating target proteins, which earmark them for degradation by the ubiquitin–proteasomal system. Prominent targets of the catalytic activity of TNKS1/2 include AXIN proteins, resulting in TNKS1/2 being attractive biotargets for addressing of oncogenic WNT/β-catenin signaling. Although several potent small molecules have been developed to inhibit TNKS1/2, there are currently no TNKS1/2 inhibitors available in clinical practice. The development of tankyrase inhibitors has mainly been disadvantaged by concerns over biotarget-dependent intestinal toxicity and a deficient therapeutic window. Here we show that the novel, potent, and selective 1,2,4-triazole–based TNKS1/2 inhibitor OM-153 reduces WNT/β-catenin signaling and tumor progression in COLO 320DM colon carcinoma xenografts upon oral administration of 0.33–10 mg/kg twice daily. In addition, OM-153 potentiates anti–programmed cell death protein 1 (anti–PD-1) immune checkpoint inhibition and antitumor effect in a B16-F10 mouse melanoma model. A 28-day repeated dose mouse toxicity study documents body weight loss, intestinal damage, and tubular damage in the kidney after oral–twice daily administration of 100 mg/kg. In contrast, mice treated oral–twice daily with 10 mg/kg show an intact intestinal architecture and no atypical histopathologic changes in other organs. In addition, clinical biochemistry and hematologic analyses do not identify changes indicating substantial toxicity. The results demonstrate OM-153–mediated antitumor effects and a therapeutic window in a colon carcinoma mouse model ranging from 0.33 to at least 10 mg/kg, and provide a framework for using OM-153 for further preclinical evaluations.

Significance: This study uncovers the effectiveness and therapeutic window for a novel tankyrase inhibitor in mouse tumor models.

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Series: Cancer research communications
ISSN: 2767-9764
ISSN-E: 2767-9764
ISSN-L: 2767-9764
Volume: 2
Issue: 4
Pages: 233 - 245
DOI: 10.1158/2767-9764.crc-22-0027
OADOI: https://oadoi.org/10.1158/2767-9764.crc-22-0027
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Subjects:
Funding: S.A. Brinch and J. Waaler were supported by the South-Eastern Norway Regional Health Authority (grant nos. 2019090 and 2021035). S. Krauss was supported by the Research Council of Norway (grant nos. 262613, 267639) and by the South-Eastern Norway Regional Health Authority (grant nos. 16/00528–9, 15/00779–2, 2015012). L. Lehtiö, S.T. Sowa, and A.Galera-Prat were supported by the Jane and Aatos Erkko Foundation. We thank the NIH and NCI for performing the NCI-60 Human Tumor Cell Lines Screening.
Copyright information: © 2022 The Authors; Published by the American Association for Cancer Research. This open access article is distributed under the Creative Commons Attribution License 4.0 International (CC BY).
  https://creativecommons.org/licenses/by/4.0/