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MTH1 inhibitor TH1579 induces oxidative DNA damage and mitotic arrest in acute myeloid leukemia

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Harvard

Sanjiv, K, Calderón-Montaño, JM, Pham, TM, Erkers, T, Tsuber, V, Almlöf, I, Höglund, A, Heshmati, Y, Seashore-Ludlow, B, Nagesh Danda, A, Gad, H, Wiita, E, Göktürk, C, Rasti, A, Friedrich, S, Centio, A, Estruch, M, Våtsveen, TK, Struyf, N, Visnes, T, Scobie, M, Koolmeister, T, Henriksson, M, Wallner, O, Sandvall, T, Lehmann, S, Theilgaard-Mönch, K, Garnett, MJ, Östling, P, Walfridsson, J, Helleday, T & Warpman Berglund, U 2021, 'MTH1 inhibitor TH1579 induces oxidative DNA damage and mitotic arrest in acute myeloid leukemia', Cancer Research. https://doi.org/10.1158/0008-5472.CAN-21-0061

APA

Sanjiv, K., Calderón-Montaño, J. M., Pham, T. M., Erkers, T., Tsuber, V., Almlöf, I., Höglund, A., Heshmati, Y., Seashore-Ludlow, B., Nagesh Danda, A., Gad, H., Wiita, E., Göktürk, C., Rasti, A., Friedrich, S., Centio, A., Estruch, M., Våtsveen, T. K., Struyf, N., ... Warpman Berglund, U. (2021). MTH1 inhibitor TH1579 induces oxidative DNA damage and mitotic arrest in acute myeloid leukemia. Cancer Research. https://doi.org/10.1158/0008-5472.CAN-21-0061

CBE

Sanjiv K, Calderón-Montaño JM, Pham TM, Erkers T, Tsuber V, Almlöf I, Höglund A, Heshmati Y, Seashore-Ludlow B, Nagesh Danda A, Gad H, Wiita E, Göktürk C, Rasti A, Friedrich S, Centio A, Estruch M, Våtsveen TK, Struyf N, Visnes T, Scobie M, Koolmeister T, Henriksson M, Wallner O, Sandvall T, Lehmann S, Theilgaard-Mönch K, Garnett MJ, Östling P, Walfridsson J, Helleday T, Warpman Berglund U. 2021. MTH1 inhibitor TH1579 induces oxidative DNA damage and mitotic arrest in acute myeloid leukemia. Cancer Research. https://doi.org/10.1158/0008-5472.CAN-21-0061

MLA

Vancouver

Author

Sanjiv, Kumar ; Calderón-Montaño, José Manuel ; Pham, Therese M ; Erkers, Tom ; Tsuber, Viktoriia ; Almlöf, Ingrid ; Höglund, Andreas ; Heshmati, Yaser ; Seashore-Ludlow, Brinton ; Nagesh Danda, Akhilesh ; Gad, Helge ; Wiita, Elisee ; Göktürk, Camilla ; Rasti, Azita ; Friedrich, Stefanie ; Centio, Anders ; Estruch, Montserrat ; Våtsveen, Thea Kristin ; Struyf, Nona ; Visnes, Torkild ; Scobie, Martin ; Koolmeister, Tobias ; Henriksson, Martin ; Wallner, Olov ; Sandvall, Teresa ; Lehmann, Sören ; Theilgaard-Mönch, Kim ; Garnett, Mathew J ; Östling, Päivi ; Walfridsson, Julian ; Helleday, Thomas ; Warpman Berglund, Ulrika. / MTH1 inhibitor TH1579 induces oxidative DNA damage and mitotic arrest in acute myeloid leukemia. I: Cancer Research. 2021.

Bibtex

@article{204df44f015445bc9042328e38749bb0,
title = "MTH1 inhibitor TH1579 induces oxidative DNA damage and mitotic arrest in acute myeloid leukemia",
abstract = "Acute myeloid leukemia (AML) is an aggressive hematological 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 hematological 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 doxorubicin. 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 pre-clinical data presented here support that TH1579 is a promising novel anticancer agent for AML, providing a rational to investigate the clinical usefulness of TH1579 in AML in an on-going clinical phase 1 trial.",
author = "Kumar Sanjiv and Calder{\'o}n-Monta{\~n}o, {Jos{\'e} Manuel} and Pham, {Therese M} and Tom Erkers and Viktoriia Tsuber and Ingrid Alml{\"o}f and Andreas H{\"o}glund and Yaser Heshmati and Brinton Seashore-Ludlow and {Nagesh Danda}, Akhilesh and Helge Gad and Elisee Wiita and Camilla G{\"o}kt{\"u}rk and Azita Rasti and Stefanie Friedrich and Anders Centio and Montserrat Estruch and V{\aa}tsveen, {Thea Kristin} and Nona Struyf and Torkild Visnes and Martin Scobie and Tobias Koolmeister and Martin Henriksson and Olov Wallner and Teresa Sandvall and S{\"o}ren Lehmann and Kim Theilgaard-M{\"o}nch and Garnett, {Mathew J} and P{\"a}ivi {\"O}stling and Julian Walfridsson and Thomas Helleday and {Warpman Berglund}, Ulrika",
year = "2021",
month = sep,
day = "30",
doi = "10.1158/0008-5472.CAN-21-0061",
language = "English",
journal = "Journal of Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research (A A C R)",

}

RIS

TY - JOUR

T1 - MTH1 inhibitor TH1579 induces oxidative DNA damage and mitotic arrest in acute myeloid leukemia

AU - Sanjiv, Kumar

AU - Calderón-Montaño, José Manuel

AU - Pham, Therese M

AU - Erkers, Tom

AU - Tsuber, Viktoriia

AU - Almlöf, Ingrid

AU - Höglund, Andreas

AU - Heshmati, Yaser

AU - Seashore-Ludlow, Brinton

AU - Nagesh Danda, Akhilesh

AU - Gad, Helge

AU - Wiita, Elisee

AU - Göktürk, Camilla

AU - Rasti, Azita

AU - Friedrich, Stefanie

AU - Centio, Anders

AU - Estruch, Montserrat

AU - Våtsveen, Thea Kristin

AU - Struyf, Nona

AU - Visnes, Torkild

AU - Scobie, Martin

AU - Koolmeister, Tobias

AU - Henriksson, Martin

AU - Wallner, Olov

AU - Sandvall, Teresa

AU - Lehmann, Sören

AU - Theilgaard-Mönch, Kim

AU - Garnett, Mathew J

AU - Östling, Päivi

AU - Walfridsson, Julian

AU - Helleday, Thomas

AU - Warpman Berglund, Ulrika

PY - 2021/9/30

Y1 - 2021/9/30

N2 - Acute myeloid leukemia (AML) is an aggressive hematological 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 hematological 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 doxorubicin. 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 pre-clinical data presented here support that TH1579 is a promising novel anticancer agent for AML, providing a rational to investigate the clinical usefulness of TH1579 in AML in an on-going clinical phase 1 trial.

AB - Acute myeloid leukemia (AML) is an aggressive hematological 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 hematological 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 doxorubicin. 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 pre-clinical data presented here support that TH1579 is a promising novel anticancer agent for AML, providing a rational to investigate the clinical usefulness of TH1579 in AML in an on-going clinical phase 1 trial.

U2 - 10.1158/0008-5472.CAN-21-0061

DO - 10.1158/0008-5472.CAN-21-0061

M3 - Journal article

C2 - 34593524

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0008-5472

ER -

ID: 68208182