Karonudib has potent anti-tumor effects in preclinical models of B-cell lymphoma

Abstract Chemo-immunotherapy has improved survival in B-cell lymphoma patients, but refractory/relapsed diseases still represent a major challenge, urging for development of new therapeutics. Karonudib (TH1579) was developed to inhibit MTH1, an enzyme preventing oxidized dNTP-incorporation in DNA. M...

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Autores principales:	Morten P. Oksvold, Ulrika Warpman Berglund, Helge Gad, Baoyan Bai, Trond Stokke, Idun Dale Rein, Therese Pham, Kumar Sanjiv, Geir Frode Øy, Jens Henrik Norum, Erlend B. Smeland, June H. Myklebust, Thomas Helleday, Thea Kristin Våtsveen
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2bf70b7f4423442fb0d96f1650f44291
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spelling	oai:doaj.org-article:2bf70b7f4423442fb0d96f1650f442912021-12-02T11:39:33ZKaronudib has potent anti-tumor effects in preclinical models of B-cell lymphoma10.1038/s41598-021-85613-82045-2322https://doaj.org/article/2bf70b7f4423442fb0d96f1650f442912021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-85613-8https://doaj.org/toc/2045-2322Abstract Chemo-immunotherapy has improved survival in B-cell lymphoma patients, but refractory/relapsed diseases still represent a major challenge, urging for development of new therapeutics. Karonudib (TH1579) was developed to inhibit MTH1, an enzyme preventing oxidized dNTP-incorporation in DNA. MTH1 is highly upregulated in tumor biopsies from patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma, hence confirming a rationale for targeting MTH1. Here, we tested the efficacy of karonudib in vitro and in preclinical B-cell lymphoma models. Using a range of B-cell lymphoma cell lines, karonudib strongly reduced viability at concentrations well tolerated by activated normal B cells. In B-cell lymphoma cells, karonudib increased incorporation of 8-oxo-dGTP into DNA, and prominently induced prometaphase arrest and apoptosis due to failure in spindle assembly. MTH1 knockout cell lines were less sensitive to karonudib-induced apoptosis, but were displaying cell cycle arrest phenotype similar to the wild type cells, indicating a dual inhibitory role of the drug. Karonudib was highly potent as single agent in two different lymphoma xenograft models, including an ABC DLBCL patient derived xenograft, leading to prolonged survival and fully controlled tumor growth. Together, our preclinical findings provide a rationale for further clinical testing of karonudib in B-cell lymphoma.Morten P. OksvoldUlrika Warpman BerglundHelge GadBaoyan BaiTrond StokkeIdun Dale ReinTherese PhamKumar SanjivGeir Frode ØyJens Henrik NorumErlend B. SmelandJune H. MyklebustThomas HelledayThea Kristin VåtsveenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Morten P. Oksvold Ulrika Warpman Berglund Helge Gad Baoyan Bai Trond Stokke Idun Dale Rein Therese Pham Kumar Sanjiv Geir Frode Øy Jens Henrik Norum Erlend B. Smeland June H. Myklebust Thomas Helleday Thea Kristin Våtsveen Karonudib has potent anti-tumor effects in preclinical models of B-cell lymphoma
description	Abstract Chemo-immunotherapy has improved survival in B-cell lymphoma patients, but refractory/relapsed diseases still represent a major challenge, urging for development of new therapeutics. Karonudib (TH1579) was developed to inhibit MTH1, an enzyme preventing oxidized dNTP-incorporation in DNA. MTH1 is highly upregulated in tumor biopsies from patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma, hence confirming a rationale for targeting MTH1. Here, we tested the efficacy of karonudib in vitro and in preclinical B-cell lymphoma models. Using a range of B-cell lymphoma cell lines, karonudib strongly reduced viability at concentrations well tolerated by activated normal B cells. In B-cell lymphoma cells, karonudib increased incorporation of 8-oxo-dGTP into DNA, and prominently induced prometaphase arrest and apoptosis due to failure in spindle assembly. MTH1 knockout cell lines were less sensitive to karonudib-induced apoptosis, but were displaying cell cycle arrest phenotype similar to the wild type cells, indicating a dual inhibitory role of the drug. Karonudib was highly potent as single agent in two different lymphoma xenograft models, including an ABC DLBCL patient derived xenograft, leading to prolonged survival and fully controlled tumor growth. Together, our preclinical findings provide a rationale for further clinical testing of karonudib in B-cell lymphoma.
format	article
author	Morten P. Oksvold Ulrika Warpman Berglund Helge Gad Baoyan Bai Trond Stokke Idun Dale Rein Therese Pham Kumar Sanjiv Geir Frode Øy Jens Henrik Norum Erlend B. Smeland June H. Myklebust Thomas Helleday Thea Kristin Våtsveen
author_facet	Morten P. Oksvold Ulrika Warpman Berglund Helge Gad Baoyan Bai Trond Stokke Idun Dale Rein Therese Pham Kumar Sanjiv Geir Frode Øy Jens Henrik Norum Erlend B. Smeland June H. Myklebust Thomas Helleday Thea Kristin Våtsveen
author_sort	Morten P. Oksvold
title	Karonudib has potent anti-tumor effects in preclinical models of B-cell lymphoma
title_short	Karonudib has potent anti-tumor effects in preclinical models of B-cell lymphoma
title_full	Karonudib has potent anti-tumor effects in preclinical models of B-cell lymphoma
title_fullStr	Karonudib has potent anti-tumor effects in preclinical models of B-cell lymphoma
title_full_unstemmed	Karonudib has potent anti-tumor effects in preclinical models of B-cell lymphoma
title_sort	karonudib has potent anti-tumor effects in preclinical models of b-cell lymphoma
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/2bf70b7f4423442fb0d96f1650f44291
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Karonudib has potent anti-tumor effects in preclinical models of B-cell lymphoma

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