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

Front Oncol. 2022 May 23:12:863329. doi: 10.3389/fonc.2022.863329. eCollection 2022.

Authors

Lin Xiao^{1

2}, Mawar Karsa^{1

2}, Emma Ronca¹, Angelika Bongers¹, Angelika Kosciolek¹, Ali El-Ayoubi¹, Jezrael L Revalde^{1

3}, Janith A Seneviratne^{1

2}, Belamy B Cheung^{1

2}, Laurence C Cheung^{4

5

6}, Rishi S Kotecha^{4

5

7

8}, Andrea Newbold^{9

10}, Stefan Bjelosevic^{9

10}, Greg M Arndt^{1

2

3}, Richard B Lock^{1

2}, Ricky W Johnstone^{9

10}, Andrei V Gudkov¹¹, Katerina V Gurova¹¹, Michelle Haber^{1

2}, Murray D Norris^{1

2

12}, Michelle J Henderson^{1

2}, Klaartje Somers^{1

2}

Affiliations

¹ Children's Cancer Institute, Lowy Cancer Research Institute, University of New South Wales, Randwick, NSW, Australia.
² School of Women's and Children's Health, University of New South Wales, Randwick, NSW, Australia.
³ Australian Cancer Research Foundation (ACRF) Drug Discovery Centre for Childhood Cancer, Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia.
⁴ Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, Australia.
⁵ Curtin Medical School, Curtin University, Perth, WA, Australia.
⁶ Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia.
⁷ Department of Clinical Haematology, Oncology, Blood and Marrow Transplantation, Perth Children's Hospital, Perth, WA, Australia.
⁸ Division of Paediatrics, School of Medicine, University of Western Australia, Perth, WA, Australia.
⁹ Gene Regulation Laboratory, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
¹⁰ The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.
¹¹ Department of Cell Stress Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, United States.
¹² University of New South Wales Centre for Childhood Cancer Research, Sydney, NSW, Australia.

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.

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.