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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. 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.

SUBMITTER: Oksvold MP

PROVIDER: S-EPMC7973795 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

Oksvold Morten P MP Berglund Ulrika Warpman UW Gad Helge H Bai Baoyan B Stokke Trond T Rein Idun Dale ID Pham Therese T Sanjiv Kumar K Øy Geir Frode GF Norum Jens Henrik JH Smeland Erlend B EB Myklebust June H JH Helleday Thomas T Våtsveen Thea Kristin TK

Scientific reports 20210318 1

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 karon ...[more]

PMID: 33737576

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Project description:Abstract BACKGROUND Atypical teratoid/rhabdoid tumors (AT/RTs) are rare pediatric brain tumors affecting mainly infants and young children. However, AT/RTs encompass almost 10% of death caused by pediatric brain tumors, and the 2-year overall survival for these children remains below 20%. For this reason, AT/RT ranks among the deadliest pediatric brain tumors. Therefore, it is clear we need to find out new therapeutic options for these children. Delta-24-RGD is an oncolytic adenovirus that has already demonstrated its efficacy as in Phase I/II clinical trials in adult patients affected by high grade gliomas with no evidence of severe side effects. Of interest for pediatric brain tumors, the safety of Delta-24-RGD is has also been demonstrated in an ongoing Phase I clinical trial for the treatment of DIPGs (NCT03178032). For these reasons, we propose to evaluate the anti-tumor effect of Delta-24-RGD in preclinical models of ATRT. MATERIAL AND METHODS Our studies have been carried out in three stablished AT/RT cell lines (BT-12, CHLA-06 and CHLA-266). In vitro, AT/RT cultures were infected with Delta-24-RGD-GFP to confirm the infectivity of the virus by flow cytometry. Replication of Delta-24-RGD was ensured by titrating the PFUs generated in AT/RT infected cultures. In regard to cytolytic effect, viability assays (MTS) were conducted in AT/RT cultures infected at increasing MOIs of Delta-24-RGD. In vivo, AT/RT cell lines were engrafted in Rag-2 mice in supratentorial and infratentorial locations, and the animals were treated with Delta-24-RGD at 107 or 108 PFU/animal (intra-tumor administration), or PBS. The therapeutic benefit of Delta-24-RGD was evaluated comparing the overall survival obtained for treated and untreated animals using the Log-rank test. We have also generated models of disseminated disease through intraventricular injection of the tumor cells, thus mimicking the lesions found in patients. AT/RT cell lines were transduced with a luc-expressing lentivirus to facilitate the follow up of these tumors. Mice bearing disseminated AT/RT were treated with Delta-24-RGD at 107 or 108 PFU/animal, or PBS (control). The therapeutic effect was monitored by bioluminescence and by comparison of the survival curves (Log-rank). RESULTS The virus was able to infect and replicate in tumor three different cell culture models of AT/RT, inducing a potent cytotoxic effect that resulting in IC50 values below 1 PFU/cell. Administration of the virus in mice bearing localized AT/RT (supratentorial and infratentorial) extended significantly the survival the animals, leading to up to 20% of long-term survivors. In disseminated AT/RT models, light emission reveals reduction of tumor growth in virus treated animals, resulting in an increased overall survival. CONCLUSION In conclusion, these results demonstrate that Delta-24-RGD could be a feasible therapeutic choice for patients affected by AT/RT.

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

Publications

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

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