Potent antileukemic activity of curaxin CBL0137 against MLL-rearranged leukemia

Klaartje Somers, Angelika Kosciolek, Angelika Bongers, Ali El-Ayoubi, Mawar Karsa, Chelsea Mayoh, Carol Wadham, Shiloh Middlemiss, Nickolay Neznanov, Ursula R. Kees, Richard B. Lock, Andrei Gudkov, Rosemary Sutton, Katerina Gurova, Michelle Haber, Murray D. Norris, Michelle J. Henderson

Research output: Contribution to journalArticle

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Abstract

Around 10% of acute leukemias harbor a rearrangement of the MLL/KMT2A gene, and the presence of this translocation results in a highly aggressive, therapy-resistant leukemia subtype with survival rates below 50%. There is a high unmet need to identify safer and more potent therapies for MLL-rearranged (MLL-r) leukemia that can be combined with established chemotherapeutics to decrease treatment-related toxicities. The curaxin, CBL0137, has demonstrated nongenotoxic anticancer and chemopotentiating effects in a number of preclinical cancer models and is currently in adult Phase I clinical trials for solid tumors and hematological malignancies. The aim of our study was to investigate whether CBL0137 has potential as a therapeutic and chemopotentiating compound in MLL-r leukemia through a comprehensive analysis of its efficacy in preclinical models of the disease. CBL0137 decreased the viability of a panel of MLL-r leukemia cell lines (n = 12) and xenograft cells derived from patients with MLL-r acute lymphoblastic leukemia (ALL, n = 3) in vitro with submicromolar IC50s. The small molecule drug was well-tolerated in vivo and significantly reduced leukemia burden in a subcutaneous MV4;11 MLL-r acute myeloid leukemia model and in patient-derived xenograft models of MLL-r ALL (n = 5). The in vivo efficacy of standard of care drugs used in remission induction for pediatric ALL was also potentiated by CBL0137. CBL0137 exerted its anticancer effect by trapping Facilitator of Chromatin Transcription (FACT) into chromatin, activating the p53 pathway and inducing an Interferon response. Our findings support further preclinical evaluation of CBL0137 as a new approach for the treatment of MLL-r leukemia.

Original languageEnglish
JournalInternational Journal of Cancer
DOIs
Publication statusE-pub ahead of print - 20 Jul 2019

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Leukemia
Heterografts
Chromatin
Therapeutics
Remission Induction
Clinical Trials, Phase I
Hematologic Neoplasms
Standard of Care
CBLC137
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Acute Myeloid Leukemia
Pharmaceutical Preparations
Interferons
Neoplasms
Survival Rate
Pediatrics
Cell Line
Genes

Cite this

Somers, K., Kosciolek, A., Bongers, A., El-Ayoubi, A., Karsa, M., Mayoh, C., ... Henderson, M. J. (2019). Potent antileukemic activity of curaxin CBL0137 against MLL-rearranged leukemia. International Journal of Cancer. https://doi.org/10.1002/ijc.32582
Somers, Klaartje ; Kosciolek, Angelika ; Bongers, Angelika ; El-Ayoubi, Ali ; Karsa, Mawar ; Mayoh, Chelsea ; Wadham, Carol ; Middlemiss, Shiloh ; Neznanov, Nickolay ; Kees, Ursula R. ; Lock, Richard B. ; Gudkov, Andrei ; Sutton, Rosemary ; Gurova, Katerina ; Haber, Michelle ; Norris, Murray D. ; Henderson, Michelle J. / Potent antileukemic activity of curaxin CBL0137 against MLL-rearranged leukemia. In: International Journal of Cancer. 2019.
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abstract = "Around 10{\%} of acute leukemias harbor a rearrangement of the MLL/KMT2A gene, and the presence of this translocation results in a highly aggressive, therapy-resistant leukemia subtype with survival rates below 50{\%}. There is a high unmet need to identify safer and more potent therapies for MLL-rearranged (MLL-r) leukemia that can be combined with established chemotherapeutics to decrease treatment-related toxicities. The curaxin, CBL0137, has demonstrated nongenotoxic anticancer and chemopotentiating effects in a number of preclinical cancer models and is currently in adult Phase I clinical trials for solid tumors and hematological malignancies. The aim of our study was to investigate whether CBL0137 has potential as a therapeutic and chemopotentiating compound in MLL-r leukemia through a comprehensive analysis of its efficacy in preclinical models of the disease. CBL0137 decreased the viability of a panel of MLL-r leukemia cell lines (n = 12) and xenograft cells derived from patients with MLL-r acute lymphoblastic leukemia (ALL, n = 3) in vitro with submicromolar IC50s. The small molecule drug was well-tolerated in vivo and significantly reduced leukemia burden in a subcutaneous MV4;11 MLL-r acute myeloid leukemia model and in patient-derived xenograft models of MLL-r ALL (n = 5). The in vivo efficacy of standard of care drugs used in remission induction for pediatric ALL was also potentiated by CBL0137. CBL0137 exerted its anticancer effect by trapping Facilitator of Chromatin Transcription (FACT) into chromatin, activating the p53 pathway and inducing an Interferon response. Our findings support further preclinical evaluation of CBL0137 as a new approach for the treatment of MLL-r leukemia.",
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Somers, K, Kosciolek, A, Bongers, A, El-Ayoubi, A, Karsa, M, Mayoh, C, Wadham, C, Middlemiss, S, Neznanov, N, Kees, UR, Lock, RB, Gudkov, A, Sutton, R, Gurova, K, Haber, M, Norris, MD & Henderson, MJ 2019, 'Potent antileukemic activity of curaxin CBL0137 against MLL-rearranged leukemia' International Journal of Cancer. https://doi.org/10.1002/ijc.32582

Potent antileukemic activity of curaxin CBL0137 against MLL-rearranged leukemia. / Somers, Klaartje; Kosciolek, Angelika; Bongers, Angelika; El-Ayoubi, Ali; Karsa, Mawar; Mayoh, Chelsea; Wadham, Carol; Middlemiss, Shiloh; Neznanov, Nickolay; Kees, Ursula R.; Lock, Richard B.; Gudkov, Andrei; Sutton, Rosemary; Gurova, Katerina; Haber, Michelle; Norris, Murray D.; Henderson, Michelle J.

In: International Journal of Cancer, 20.07.2019.

Research output: Contribution to journalArticle

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T1 - Potent antileukemic activity of curaxin CBL0137 against MLL-rearranged leukemia

AU - Somers, Klaartje

AU - Kosciolek, Angelika

AU - Bongers, Angelika

AU - El-Ayoubi, Ali

AU - Karsa, Mawar

AU - Mayoh, Chelsea

AU - Wadham, Carol

AU - Middlemiss, Shiloh

AU - Neznanov, Nickolay

AU - Kees, Ursula R.

AU - Lock, Richard B.

AU - Gudkov, Andrei

AU - Sutton, Rosemary

AU - Gurova, Katerina

AU - Haber, Michelle

AU - Norris, Murray D.

AU - Henderson, Michelle J.

PY - 2019/7/20

Y1 - 2019/7/20

N2 - Around 10% of acute leukemias harbor a rearrangement of the MLL/KMT2A gene, and the presence of this translocation results in a highly aggressive, therapy-resistant leukemia subtype with survival rates below 50%. There is a high unmet need to identify safer and more potent therapies for MLL-rearranged (MLL-r) leukemia that can be combined with established chemotherapeutics to decrease treatment-related toxicities. The curaxin, CBL0137, has demonstrated nongenotoxic anticancer and chemopotentiating effects in a number of preclinical cancer models and is currently in adult Phase I clinical trials for solid tumors and hematological malignancies. The aim of our study was to investigate whether CBL0137 has potential as a therapeutic and chemopotentiating compound in MLL-r leukemia through a comprehensive analysis of its efficacy in preclinical models of the disease. CBL0137 decreased the viability of a panel of MLL-r leukemia cell lines (n = 12) and xenograft cells derived from patients with MLL-r acute lymphoblastic leukemia (ALL, n = 3) in vitro with submicromolar IC50s. The small molecule drug was well-tolerated in vivo and significantly reduced leukemia burden in a subcutaneous MV4;11 MLL-r acute myeloid leukemia model and in patient-derived xenograft models of MLL-r ALL (n = 5). The in vivo efficacy of standard of care drugs used in remission induction for pediatric ALL was also potentiated by CBL0137. CBL0137 exerted its anticancer effect by trapping Facilitator of Chromatin Transcription (FACT) into chromatin, activating the p53 pathway and inducing an Interferon response. Our findings support further preclinical evaluation of CBL0137 as a new approach for the treatment of MLL-r leukemia.

AB - Around 10% of acute leukemias harbor a rearrangement of the MLL/KMT2A gene, and the presence of this translocation results in a highly aggressive, therapy-resistant leukemia subtype with survival rates below 50%. There is a high unmet need to identify safer and more potent therapies for MLL-rearranged (MLL-r) leukemia that can be combined with established chemotherapeutics to decrease treatment-related toxicities. The curaxin, CBL0137, has demonstrated nongenotoxic anticancer and chemopotentiating effects in a number of preclinical cancer models and is currently in adult Phase I clinical trials for solid tumors and hematological malignancies. The aim of our study was to investigate whether CBL0137 has potential as a therapeutic and chemopotentiating compound in MLL-r leukemia through a comprehensive analysis of its efficacy in preclinical models of the disease. CBL0137 decreased the viability of a panel of MLL-r leukemia cell lines (n = 12) and xenograft cells derived from patients with MLL-r acute lymphoblastic leukemia (ALL, n = 3) in vitro with submicromolar IC50s. The small molecule drug was well-tolerated in vivo and significantly reduced leukemia burden in a subcutaneous MV4;11 MLL-r acute myeloid leukemia model and in patient-derived xenograft models of MLL-r ALL (n = 5). The in vivo efficacy of standard of care drugs used in remission induction for pediatric ALL was also potentiated by CBL0137. CBL0137 exerted its anticancer effect by trapping Facilitator of Chromatin Transcription (FACT) into chromatin, activating the p53 pathway and inducing an Interferon response. Our findings support further preclinical evaluation of CBL0137 as a new approach for the treatment of MLL-r leukemia.

KW - CBL0137

KW - interferon

KW - mixed-lineage leukemia

KW - p53

KW - patient-derived xenograft

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U2 - 10.1002/ijc.32582

DO - 10.1002/ijc.32582

M3 - Article

JO - International Journal of Cancer (Predictive Oncology)

JF - International Journal of Cancer (Predictive Oncology)

SN - 0020-7136

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