The Combination of Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Delays KMT2A-Rearranged Leukemia Progression

Lin Xiao; Mawar Karsa; Emma Ronca; Angelika Bongers; Angelika Kosciolek; Ali El-Ayoubi; Jezrael L. Revalde; Janith A. Seneviratne; Belamy B. Cheung; Laurence C. Cheung; Rishi S. Kotecha; Andrea Newbold; Stefan Bjelosevic; Greg M. Arndt; Richard B. Lock; Ricky W. Johnstone; Andrei V. Gudkov; Katerina V. Gurova; Michelle Haber; Murray D. Norris; Michelle J. Henderson; Klaartje Somers

doi:10.3389/fonc.2022.863329

The Combination of Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Delays KMT2A-Rearranged Leukemia Progression

Lin Xiao
, Mawar Karsa
, Emma Ronca
, Angelika Bongers
, Angelika Kosciolek
, Ali El-Ayoubi
, Jezrael L. Revalde
, Janith A. Seneviratne
, Belamy B. Cheung
, Laurence C. Cheung
, Rishi S. Kotecha
, Andrea Newbold
, Stefan Bjelosevic
, Greg M. Arndt
, Richard B. Lock
, Ricky W. Johnstone
, Andrei V. Gudkov
, Katerina V. Gurova
, Michelle Haber
, Murray D. Norris

Michelle J. Henderson, Klaartje Somers

Roswell Park - Cell Stress and Biophysical Oncology

University of New South Wales
the University of Western Australia
Curtin University
Perth Children's Hospital
University of Western Australia
Peter Maccallum Cancer Centre
University of Melbourne
Roswell Park Cancer Institute

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

Abstract

Rearrangements of the Mixed Lineage Leukemia (MLL/KMT2A) gene are present in approximately 10% of acute leukemias and characteristically define disease with poor outcome. Driven by the unmet need to develop better therapies for KMT2A-rearranged leukemia, we previously discovered that the novel anti-cancer agent, curaxin CBL0137, induces decondensation of chromatin in cancer cells, delays leukemia progression and potentiates standard of care chemotherapies in preclinical KMT2A-rearranged leukemia models. Based on the promising potential of histone deacetylase (HDAC) inhibitors as targeted anti-cancer agents for KMT2A-rearranged leukemia and the fact that HDAC inhibitors also decondense chromatin via an alternate mechanism, we investigated whether CBL0137 could potentiate the efficacy of the HDAC inhibitor panobinostat in KMT2A-rearranged leukemia models. The combination of CBL0137 and panobinostat rapidly killed KMT2A-rearranged leukemia cells by apoptosis and significantly delayed leukemia progression and extended survival in an aggressive model of MLL-AF9 (KMT2A:MLLT3) driven murine acute myeloid leukemia. The drug combination also exerted a strong anti-leukemia response in a rapidly progressing xenograft model derived from an infant with KMT2A-rearranged acute lymphoblastic leukemia, significantly extending survival compared to either monotherapy. The therapeutic enhancement between CBL0137 and panobinostat in KMT2A-r leukemia cells does not appear to be mediated through cooperative effects of the drugs on KMT2A rearrangement-associated histone modifications. Our data has identified the CBL0137/panobinostat combination as a potential novel targeted therapeutic approach to improve outcome for KMT2A-rearranged leukemia.

Original language	English
Article number	863329
Journal	Frontiers in Oncology
Volume	12
DOIs	https://doi.org/10.3389/fonc.2022.863329
State	Published - May 23 2022

Keywords

KMT2A-rearranged leukemia
chromatin
curaxin CBL0137
histone deacetylase inhibition
infant leukemia

Access to Document

10.3389/fonc.2022.863329

Cite this

Xiao, L., Karsa, M., Ronca, E., Bongers, A., Kosciolek, A., El-Ayoubi, A., Revalde, J. L., Seneviratne, J. A., Cheung, B. B., Cheung, L. C., Kotecha, R. S., Newbold, A., Bjelosevic, S., Arndt, G. M., Lock, R. B., Johnstone, R. W., Gudkov, A. V., Gurova, K. V., Haber, M., ... Somers, K. (2022). The Combination of Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Delays KMT2A-Rearranged Leukemia Progression. Frontiers in Oncology, 12, Article 863329. https://doi.org/10.3389/fonc.2022.863329

@article{a73da3f57c16465298a85c5e7eba5b50,

title = "The Combination of Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Delays KMT2A-Rearranged Leukemia Progression",

abstract = "Rearrangements of the Mixed Lineage Leukemia (MLL/KMT2A) gene are present in approximately 10\% of acute leukemias and characteristically define disease with poor outcome. Driven by the unmet need to develop better therapies for KMT2A-rearranged leukemia, we previously discovered that the novel anti-cancer agent, curaxin CBL0137, induces decondensation of chromatin in cancer cells, delays leukemia progression and potentiates standard of care chemotherapies in preclinical KMT2A-rearranged leukemia models. Based on the promising potential of histone deacetylase (HDAC) inhibitors as targeted anti-cancer agents for KMT2A-rearranged leukemia and the fact that HDAC inhibitors also decondense chromatin via an alternate mechanism, we investigated whether CBL0137 could potentiate the efficacy of the HDAC inhibitor panobinostat in KMT2A-rearranged leukemia models. The combination of CBL0137 and panobinostat rapidly killed KMT2A-rearranged leukemia cells by apoptosis and significantly delayed leukemia progression and extended survival in an aggressive model of MLL-AF9 (KMT2A:MLLT3) driven murine acute myeloid leukemia. The drug combination also exerted a strong anti-leukemia response in a rapidly progressing xenograft model derived from an infant with KMT2A-rearranged acute lymphoblastic leukemia, significantly extending survival compared to either monotherapy. The therapeutic enhancement between CBL0137 and panobinostat in KMT2A-r leukemia cells does not appear to be mediated through cooperative effects of the drugs on KMT2A rearrangement-associated histone modifications. Our data has identified the CBL0137/panobinostat combination as a potential novel targeted therapeutic approach to improve outcome for KMT2A-rearranged leukemia.",

keywords = "KMT2A-rearranged leukemia, chromatin, curaxin CBL0137, histone deacetylase inhibition, infant leukemia",

author = "Lin Xiao and Mawar Karsa and Emma Ronca and Angelika Bongers and Angelika Kosciolek and Ali El-Ayoubi and Revalde, \{Jezrael L.\} and Seneviratne, \{Janith A.\} and Cheung, \{Belamy B.\} and Cheung, \{Laurence C.\} and Kotecha, \{Rishi S.\} and Andrea Newbold and Stefan Bjelosevic and Arndt, \{Greg M.\} and Lock, \{Richard B.\} and Johnstone, \{Ricky W.\} and Gudkov, \{Andrei V.\} and Gurova, \{Katerina V.\} and Michelle Haber and Norris, \{Murray D.\} and Henderson, \{Michelle J.\} and Klaartje Somers",

note = "Publisher Copyright: Copyright {\textcopyright} 2022 Xiao, Karsa, Ronca, Bongers, Kosciolek, El-Ayoubi, Revalde, Seneviratne, Cheung, Cheung, Kotecha, Newbold, Bjelosevic, Arndt, Lock, Johnstone, Gudkov, Gurova, Haber, Norris, Henderson and Somers.",

year = "2022",

month = may,

day = "23",

doi = "10.3389/fonc.2022.863329",

language = "English",

volume = "12",

journal = "Frontiers in Oncology",

issn = "2234-943X",

publisher = "Frontiers Media SA",

}

Xiao, L, Karsa, M, Ronca, E, Bongers, A, Kosciolek, A, El-Ayoubi, A, Revalde, JL, Seneviratne, JA, Cheung, BB, Cheung, LC, Kotecha, RS, Newbold, A, Bjelosevic, S, Arndt, GM, Lock, RB, Johnstone, RW, Gudkov, AV, Gurova, KV, Haber, M, Norris, MD, Henderson, MJ & Somers, K 2022, 'The Combination of Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Delays KMT2A-Rearranged Leukemia Progression', Frontiers in Oncology, vol. 12, 863329. https://doi.org/10.3389/fonc.2022.863329

TY - JOUR

T1 - The Combination of Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Delays KMT2A-Rearranged Leukemia Progression

AU - Xiao, Lin

AU - Karsa, Mawar

AU - Ronca, Emma

AU - Bongers, Angelika

AU - Kosciolek, Angelika

AU - El-Ayoubi, Ali

AU - Revalde, Jezrael L.

AU - Seneviratne, Janith A.

AU - Cheung, Belamy B.

AU - Cheung, Laurence C.

AU - Kotecha, Rishi S.

AU - Newbold, Andrea

AU - Bjelosevic, Stefan

AU - Arndt, Greg M.

AU - Lock, Richard B.

AU - Johnstone, Ricky W.

AU - Gudkov, Andrei V.

AU - Gurova, Katerina V.

AU - Haber, Michelle

AU - Norris, Murray D.

AU - Henderson, Michelle J.

AU - Somers, Klaartje

N1 - Publisher Copyright: Copyright © 2022 Xiao, Karsa, Ronca, Bongers, Kosciolek, El-Ayoubi, Revalde, Seneviratne, Cheung, Cheung, Kotecha, Newbold, Bjelosevic, Arndt, Lock, Johnstone, Gudkov, Gurova, Haber, Norris, Henderson and Somers.

PY - 2022/5/23

Y1 - 2022/5/23

N2 - Rearrangements of the Mixed Lineage Leukemia (MLL/KMT2A) gene are present in approximately 10% of acute leukemias and characteristically define disease with poor outcome. Driven by the unmet need to develop better therapies for KMT2A-rearranged leukemia, we previously discovered that the novel anti-cancer agent, curaxin CBL0137, induces decondensation of chromatin in cancer cells, delays leukemia progression and potentiates standard of care chemotherapies in preclinical KMT2A-rearranged leukemia models. Based on the promising potential of histone deacetylase (HDAC) inhibitors as targeted anti-cancer agents for KMT2A-rearranged leukemia and the fact that HDAC inhibitors also decondense chromatin via an alternate mechanism, we investigated whether CBL0137 could potentiate the efficacy of the HDAC inhibitor panobinostat in KMT2A-rearranged leukemia models. The combination of CBL0137 and panobinostat rapidly killed KMT2A-rearranged leukemia cells by apoptosis and significantly delayed leukemia progression and extended survival in an aggressive model of MLL-AF9 (KMT2A:MLLT3) driven murine acute myeloid leukemia. The drug combination also exerted a strong anti-leukemia response in a rapidly progressing xenograft model derived from an infant with KMT2A-rearranged acute lymphoblastic leukemia, significantly extending survival compared to either monotherapy. The therapeutic enhancement between CBL0137 and panobinostat in KMT2A-r leukemia cells does not appear to be mediated through cooperative effects of the drugs on KMT2A rearrangement-associated histone modifications. Our data has identified the CBL0137/panobinostat combination as a potential novel targeted therapeutic approach to improve outcome for KMT2A-rearranged leukemia.

AB - Rearrangements of the Mixed Lineage Leukemia (MLL/KMT2A) gene are present in approximately 10% of acute leukemias and characteristically define disease with poor outcome. Driven by the unmet need to develop better therapies for KMT2A-rearranged leukemia, we previously discovered that the novel anti-cancer agent, curaxin CBL0137, induces decondensation of chromatin in cancer cells, delays leukemia progression and potentiates standard of care chemotherapies in preclinical KMT2A-rearranged leukemia models. Based on the promising potential of histone deacetylase (HDAC) inhibitors as targeted anti-cancer agents for KMT2A-rearranged leukemia and the fact that HDAC inhibitors also decondense chromatin via an alternate mechanism, we investigated whether CBL0137 could potentiate the efficacy of the HDAC inhibitor panobinostat in KMT2A-rearranged leukemia models. The combination of CBL0137 and panobinostat rapidly killed KMT2A-rearranged leukemia cells by apoptosis and significantly delayed leukemia progression and extended survival in an aggressive model of MLL-AF9 (KMT2A:MLLT3) driven murine acute myeloid leukemia. The drug combination also exerted a strong anti-leukemia response in a rapidly progressing xenograft model derived from an infant with KMT2A-rearranged acute lymphoblastic leukemia, significantly extending survival compared to either monotherapy. The therapeutic enhancement between CBL0137 and panobinostat in KMT2A-r leukemia cells does not appear to be mediated through cooperative effects of the drugs on KMT2A rearrangement-associated histone modifications. Our data has identified the CBL0137/panobinostat combination as a potential novel targeted therapeutic approach to improve outcome for KMT2A-rearranged leukemia.

KW - KMT2A-rearranged leukemia

KW - chromatin

KW - curaxin CBL0137

KW - histone deacetylase inhibition

KW - infant leukemia

UR - https://www.scopus.com/pages/publications/85131861535

U2 - 10.3389/fonc.2022.863329

DO - 10.3389/fonc.2022.863329

M3 - Article

AN - SCOPUS:85131861535

SN - 2234-943X

VL - 12

JO - Frontiers in Oncology

JF - Frontiers in Oncology

M1 - 863329

ER -

The Combination of Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Delays KMT2A-Rearranged Leukemia Progression

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this