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| Status |
Public on Dec 07, 2018 |
| Title |
Preclinical efficacy of the MTH1 inhibitor karonudib in B-cell lymphoma |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Although chemo-immunotherapy has greatly improved survival of B-cell lymphoma patients, treatment resistant and refractory disease represent a major challenge that call for development of new treatment options. Karonudib (TH1579) is a new drug developed to inhibit MTH1, an enzyme which prevents oxidized dNTPs from being incorporated into DNA. Here, we tested the efficacy of karonudib in vitro and in preclinical models of B-cell lymphoma. Karonudib reduced viability in a wide range of B-cell lymphoma cell lines at concentrations that were well tolerated by activated normal B cells. Induction of mitotic arrest was seen as early as 6 h after karonudib treatment, with induction of apoptosis detected after 12 h. These effects were observed independent of TP53 mutational status. Increased incorporation of 8-oxo-dGTP into DNA, in addition to arrest in prometaphase due to failure in spindle assembly were detected in cells exposed to karonudib, suggesting a dual inhibitory mechanism. Karonudib inhibited tumor growth, led to complete remission in the majority of cases and prolonged survival in two different xenograft mouse models of aggressive B-cell lymphoma, including an ABC DLBCL patient-derived xenograft model. Karonudib was well tolerated in vivo, and no weight loss was observed in treated animals. NUDT1, the gene encoding MTH1, was upregulated in tumor biopsies from ABC and GCB DLBCL and BL patients, as compared to B cells from healthy donors. Together, our preclinical findings provide a rational for further clinical testing of karonudib in aggressive B-cell lymphoma.
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| Overall design |
The microarray analyses were performed on GeneChip® Human Gene 2.0 ST Array (Affymetrix, Santa Barbara, CA). Two replicates were run per cell line (BL-41 and Mino) with a week apart. Gene set enrichment analysis was performed using the GSEA software v.3.0. combining both cell line data against predicted gene sets (Hallmark datasets) downloaded from the MSigDB collection. A thousand permutations were performed to test against control and karonudib treated cells. Gene sets with false discovery rate (FDR) q values < 0.1 were regarded as significantly enriched gene sets.
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| Contributor(s) |
Oksvold MP, Berglund UW, Gad H, Bai B, Stokke T, Rein ID, Pham T, Øy GF, Norum JH, Smeland EB, Myklebust JH, Helleday T, Våtsveen TK |
| Citation(s) |
33737576 |
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| Submission date |
Dec 06, 2018 |
| Last update date |
Mar 23, 2021 |
| Contact name |
Thea Kristin Vatsveen |
| Organization name |
Oslo University Hospital
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| Department |
Cancer Research
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| Lab |
Cancer Immunology
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| Street address |
Ullernschauseen 70
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| City |
Oslo |
| ZIP/Postal code |
0371 |
| Country |
Norway |
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| Platforms (1) |
| GPL16686 |
[HuGene-2_0-st] Affymetrix Human Gene 2.0 ST Array [transcript (gene) version] |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA508776 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE123449_RAW.tar |
61.0 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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