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

Morten P Oksvold1,2, Ulrika Warpman Berglund3, Helge Gad3,4

  • 1Department of Cancer Immunology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Ullernschausseen 70, 0379, Montebello, Oslo, Norway.

Scientific Reports
|March 19, 2021
PubMed

Insights

Karonudib effectively targets MTH1 in B-cell lymphomas, inducing DNA damage and cell death. Preclinical models show potent anti-tumor activity, supporting its clinical investigation for refractory/relapsed diseases.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Chemo-immunotherapy improves outcomes in B-cell lymphoma but challenges remain with refractory/relapsed disease.
  • Mutant form of Thymine DNA Glycosylase (MTH1) is upregulated in diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma, indicating its potential as a therapeutic target.
  • Karonudib (TH1579) is a novel therapeutic agent designed to inhibit MTH1, thereby preventing the incorporation of oxidized dNTPs into DNA.

Purpose of the Study:

  • To evaluate the efficacy of karonudib in vitro and in preclinical B-cell lymphoma models.
  • To investigate the mechanism of action of karonudib in B-cell lymphoma cells.
  • To assess the therapeutic potential of karonudib as a single agent in vivo.

Main Methods:

  • In vitro studies using B-cell lymphoma cell lines to assess karonudib's effect on cell viability and DNA damage.
  • Analysis of DNA incorporation of 8-oxo-dGTP, prometaphase arrest, and apoptosis induction.
  • Evaluation of MTH1 knockout cell lines to elucidate the drug's dual inhibitory role.
  • In vivo efficacy studies using lymphoma xenograft models, including patient-derived xenografts.

Main Results:

  • Karonudib significantly reduced B-cell lymphoma cell viability at well-tolerated concentrations.
  • The drug increased 8-oxo-dGTP incorporation into DNA, induced prometaphase arrest, and triggered apoptosis.
  • MTH1 knockout cells showed reduced sensitivity to karonudib-induced apoptosis but similar cell cycle arrest.
  • Karonudib demonstrated potent single-agent activity in xenograft models, prolonging survival and controlling tumor growth.

Conclusions:

  • Karonudib exhibits significant preclinical efficacy against B-cell lymphomas by targeting MTH1.
  • The drug induces DNA damage and cell cycle arrest, leading to apoptosis.
  • These findings support the further clinical evaluation of karonudib for treating B-cell lymphomas, particularly refractory/relapsed cases.

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