Frontiers in Oncology (May 2022)
The Combination of Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Delays KMT2A-Rearranged Leukemia Progression
- Lin Xiao,
- Lin Xiao,
- Mawar Karsa,
- Mawar Karsa,
- Emma Ronca,
- Angelika Bongers,
- Angelika Kosciolek,
- Ali El-Ayoubi,
- Jezrael L. Revalde,
- Jezrael L. Revalde,
- Janith A. Seneviratne,
- Janith A. Seneviratne,
- Belamy B. Cheung,
- Belamy B. Cheung,
- Laurence C. Cheung,
- Laurence C. Cheung,
- Laurence C. Cheung,
- Rishi S. Kotecha,
- Rishi S. Kotecha,
- Rishi S. Kotecha,
- Rishi S. Kotecha,
- Andrea Newbold,
- Andrea Newbold,
- Stefan Bjelosevic,
- Stefan Bjelosevic,
- Greg M. Arndt,
- Greg M. Arndt,
- Greg M. Arndt,
- Richard B. Lock,
- Richard B. Lock,
- Ricky W. Johnstone,
- Ricky W. Johnstone,
- Andrei V. Gudkov,
- Katerina V. Gurova,
- Michelle Haber,
- Michelle Haber,
- Murray D. Norris,
- Murray D. Norris,
- Murray D. Norris,
- Michelle J. Henderson,
- Michelle J. Henderson,
- Klaartje Somers,
- Klaartje Somers
Affiliations
- Lin Xiao
- Children’s Cancer Institute, Lowy Cancer Research Institute, University of New South Wales, Randwick, NSW, Australia
- Lin Xiao
- School of Women’s and Children’s Health, University of New South Wales, Randwick, NSW, Australia
- Mawar Karsa
- Children’s Cancer Institute, Lowy Cancer Research Institute, University of New South Wales, Randwick, NSW, Australia
- Mawar Karsa
- School of Women’s and Children’s Health, University of New South Wales, Randwick, NSW, Australia
- Emma Ronca
- Children’s Cancer Institute, Lowy Cancer Research Institute, University of New South Wales, Randwick, NSW, Australia
- Angelika Bongers
- Children’s Cancer Institute, Lowy Cancer Research Institute, University of New South Wales, Randwick, NSW, Australia
- Angelika Kosciolek
- Children’s Cancer Institute, Lowy Cancer Research Institute, University of New South Wales, Randwick, NSW, Australia
- Ali El-Ayoubi
- Children’s Cancer Institute, Lowy Cancer Research Institute, University of New South Wales, Randwick, NSW, Australia
- Jezrael L. Revalde
- Children’s Cancer Institute, Lowy Cancer Research Institute, University of New South Wales, Randwick, NSW, Australia
- Jezrael L. Revalde
- 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
- Janith A. Seneviratne
- Children’s Cancer Institute, Lowy Cancer Research Institute, University of New South Wales, Randwick, NSW, Australia
- Janith A. Seneviratne
- School of Women’s and Children’s Health, University of New South Wales, Randwick, NSW, Australia
- Belamy B. Cheung
- Children’s Cancer Institute, Lowy Cancer Research Institute, University of New South Wales, Randwick, NSW, Australia
- Belamy B. Cheung
- School of Women’s and Children’s Health, University of New South Wales, Randwick, NSW, Australia
- Laurence C. Cheung
- Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, Australia
- Laurence C. Cheung
- Curtin Medical School, Curtin University, Perth, WA, Australia
- Laurence C. Cheung
- Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
- Rishi S. Kotecha
- Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, Australia
- Rishi S. Kotecha
- Curtin Medical School, Curtin University, Perth, WA, Australia
- Rishi S. Kotecha
- Department of Clinical Haematology, Oncology, Blood and Marrow Transplantation, Perth Children’s Hospital, Perth, WA, Australia
- Rishi S. Kotecha
- Division of Paediatrics, School of Medicine, University of Western Australia, Perth, WA, Australia
- Andrea Newbold
- Gene Regulation Laboratory, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Andrea Newbold
- 0The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
- Stefan Bjelosevic
- Gene Regulation Laboratory, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Stefan Bjelosevic
- 0The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
- Greg M. Arndt
- Children’s Cancer Institute, Lowy Cancer Research Institute, University of New South Wales, Randwick, NSW, Australia
- Greg M. Arndt
- School of Women’s and Children’s Health, University of New South Wales, Randwick, NSW, Australia
- Greg M. Arndt
- 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
- Richard B. Lock
- Children’s Cancer Institute, Lowy Cancer Research Institute, University of New South Wales, Randwick, NSW, Australia
- Richard B. Lock
- School of Women’s and Children’s Health, University of New South Wales, Randwick, NSW, Australia
- Ricky W. Johnstone
- Gene Regulation Laboratory, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Ricky W. Johnstone
- 0The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
- Andrei V. Gudkov
- 1Department of Cell Stress Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, United States
- Katerina V. Gurova
- 1Department of Cell Stress Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, United States
- Michelle Haber
- Children’s Cancer Institute, Lowy Cancer Research Institute, University of New South Wales, Randwick, NSW, Australia
- Michelle Haber
- School of Women’s and Children’s Health, University of New South Wales, Randwick, NSW, Australia
- Murray D. Norris
- Children’s Cancer Institute, Lowy Cancer Research Institute, University of New South Wales, Randwick, NSW, Australia
- Murray D. Norris
- School of Women’s and Children’s Health, University of New South Wales, Randwick, NSW, Australia
- Murray D. Norris
- 2University of New South Wales Centre for Childhood Cancer Research, Sydney, NSW, Australia
- Michelle J. Henderson
- Children’s Cancer Institute, Lowy Cancer Research Institute, University of New South Wales, Randwick, NSW, Australia
- Michelle J. Henderson
- School of Women’s and Children’s Health, University of New South Wales, Randwick, NSW, Australia
- Klaartje Somers
- Children’s Cancer Institute, Lowy Cancer Research Institute, University of New South Wales, Randwick, NSW, Australia
- Klaartje Somers
- School of Women’s and Children’s Health, University of New South Wales, Randwick, NSW, Australia
- DOI
- https://doi.org/10.3389/fonc.2022.863329
- Journal volume & issue
-
Vol. 12
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
