期刊
CANCER RESEARCH
卷 81, 期 22, 页码 5733-5744出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-21-0061
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资金
- Wellcome Trust [206194]
- European Research Council (TAROX Programme) [ERC-695376]
- Swedish Research Council [2015-00162, 2017-06095]
- Swedish Cancer Society [CAN2018/0658]
- Torsten and Ragnar Soderberg Foundation
- Swedish Foundation for Strategic Research [RB13-0224]
- Radiumhemmets Forskningsfond [191282]
- Swedish Childhood Cancer Fund [PR2018-0095]
- Vinnova [2015-04755]
- Swedish Institute Visby [R167-A10932-17-S2]
- Danish Cancer Society [R167-A10932-17-S2]
- Swedish Research Council [2017-06095] Funding Source: Swedish Research Council
- Swedish Foundation for Strategic Research (SSF) [RB13-0224] Funding Source: Swedish Foundation for Strategic Research (SSF)
TH1579 kills AML cells by inducing mitotic arrest, increasing intracellular ROS levels, and enhancing oxidative DNA damage. It shows a significant therapeutic window, is well tolerated in animals, and can be combined with standard-of-care treatments to further improve efficacy. TH1579 significantly improves survival in two different AML disease models in vivo.
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy, exhibiting high levels of reactive oxygen species (ROS). ROS levels have been suggested to drive leukemogenesis and is thus a potential novel target for treating AML. MTH1 prevents incorporation of oxidized nucleotides into the DNA to maintain genome integrity and is upregulated in many cancers. Here we demonstrate that hematologic cancers are highly sensitive to MTH1 inhibitor TH1579 (karonudib). A functional precision medicine ex vivo screen in primary AML bone marrow samples demonstrated a broad response profile of TH1579, independent of the genomic alteration of AML, resembling the response profile of the standard-of-care treatments cytarabine and doxorubidn. Furthermore, TH1579 killed primary human AML blast cells (CD45(+)) as well as chemotherapy resistance leukemic stem cells (CD45(+) Lin(-) CD34(+) CD38(-)), which are often responsible for AML progression. TH1579 killed AML cells by causing mitotic arrest, elevating intracellular ROS levels, and enhancing oxidative DNA damage. TH1579 showed a significant therapeutic window, was well tolerated in animals, and could be combined with standard-of-care treatments to further improve efficacy. TH1579 significantly improved survival in two different AML disease models in vivo. In conclusion, the preclinical data presented here support that TH1579 is a promising novel anticancer agent for AML, providing a rationale to investigate the clinical usefulness of TH1579 in AML in an ongoing clinical phase I trial. Significance: The MTH1 inhibitor TH1579 is a potential novel AML treatment, targeting both blasts and the pivotal leukemic stem cells while sparing normal bone marrow cells.
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