Combination of the low anticoagulant heparin CX-01 with chemotherapy for the treatment of acute myeloid leukemia

Kovacsovics, Tibor; Mims, Alice S.; Salama, Mohamed E.; Pantin, Jeremy; Rao, Narayanam V.; Kosak, Ken M.; Ahorukomeye, Peter; Glenn, Martha; Deininger, Michael W.; Boucher, Kenneth M.; Bavisotto, Linda M.; Gutiérrez-Sánchez, Gerardo; Kennedy, Thomas P.; Marcus, S.; Shami, Paul J.

doi:10.1182/bloodadvances.2017013391

Cited by 47 publications

(36 citation statements)

References 40 publications

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“…Because sivelestat could also alter TLR expression, combination therapy with TLR antagonists could offer another therapeutic approach. For example, combination chemotherapy and CX-01, a TLR2/TLR4 antagonist and heparin derivative, could reduce cancer burden in early-phase studies in relapsed acute myeloid leukemia (37) and MDS (NCT02995655). These data could provide a rationale for therapeutic combinations with standard chemotherapies, HMGB1 inhibitors, and TLR antagonists.…”

Section: Discussionmentioning

confidence: 99%

Targeting High Mobility Group Box-1 (HMGB1) Promotes Cell Death in Myelodysplastic Syndrome

Kam

Piryani

McCall

et al. 2019

Clinical Cancer Research

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Purpose: Myelodysplastic syndrome (MDS) is associated with a dysregulated innate immune system. The purpose of this study was to determine whether modulation of the innate immune system via high mobility group box-1 (HMGB1) could reduce cell viability in MDS.Experimental Design: We quantified HMGB1 in an MDS cell line MDS-L and in primary MDS cells compared with nonmalignant hematopoietic cells. We performed loss-offunction studies of HMGB1 using pooled siRNAs and a small-molecule inhibitor sivelestat compared with standard chemotherapy. We measured levels of engraftment of MDS-L cells in NOD-scidIL2Rg null (NSG) mice following treatment with sivelestat. Mechanistically, we interrogated cell survival pathways and 45 targets within the NFkB pathway using both protein analysis and a proteome profiler array.Results: We discovered that HMGB1 had increased expression in both MDS-L cells and in primary CD34 þ MDS cells compared with healthy CD34 þ hematopoietic cells. Sivelestat impaired MDS cell expansion, increased cellular death, and spared healthy hematopoietic cells. MDS-L marrow engraftment is reduced significantly at 17 weeks following treatment with sivelestat compared with control mice. Treatment of CD34 þ MDS cells with sivelestat and azacitidine or decitabine was additive to increase apoptotic cell death compared with chemotherapy alone. Sivelestat promoted apoptosis with increased expression of PUMA, activated caspase 3, and increased DNA double-strand breaks. Inhibition of HMGB1 reduced levels of Toll-like receptors (TLR) and suppressed activation of NFkB in MDS-L cells.Conclusions: Inhibition of HMGB1 could promote MDS cell death and alter innate immune responses via suppression of NFkB pathways.

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Section: Discussionmentioning

confidence: 99%

Targeting High Mobility Group Box-1 (HMGB1) Promotes Cell Death in Myelodysplastic Syndrome

Kam

Piryani

McCall

et al. 2019

Clinical Cancer Research

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“…These LSCs will cause chemotherapy resistance in acute myelogenous leukemia (AML). CX-01 is a low-anticoagulant heparin derivative that can block CXCL12/CXCR4 activity and therefore disrupt the LSCs in marrow, and CX-01 has been clinically verified to promote chemotherapy efficiency in the treatment of AML [76]. In addition to affecting AML, the same mechanisms support the therapeutic potential of CX-01 for myelodysplastic syndrome, multiple myeloma, and lymphoma.…”

Section: Heparin Prevents Cancer Relapse By Inhibiting Cancer Stem Cellsmentioning

confidence: 99%

The anti-cancer properties of heparin and its derivatives: a review and prospect

Mao

et al. 2020

Cell Adhesion & Migration

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Heparin, including unfractionated heparin (UFH), low-molecular-weight heparin (LMWH) and heparin derivatives, are commonly used in venous thromboembolism treatment and reportedly have beneficial effects on cancer survival. Heparin can affect the proliferation, adhesion, angiogenesis, migration and invasion of cancer cells via multiple mechanisms. The main mechanisms involve inhibition of heparanase, P-/L-selectin, angiogenesis, and interference with the CXCL12-CXCR4 axis. Here we summarize the current experimental evidence regarding the anti-cancer role of heparin and its derivatives, and conclude that there is evidence to support heparin's role in inhibiting cancer progression, making it a promising anti-cancer agent.

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“…CX-01 was tested in a phase I pilot study in newly diagnosed patients with AML receiving cytarabine and idarubicin induction or cytarabine consolidation chemotherapy (NCT02056782). Preliminary results showed excellent morphologic CR achievement after 1 induction (92%), with median disease-free survival of 14.8 months, and median overall survival not attained at the maximum follow-up time (29.4 months) (Kovacsovics et al, 2018). Recently, a phase II study (NCT02873338) carried out by the same group in elderly patients (older than 59) confirmed a high 89% CR and CRi in patients treated with chemotherapy and high concentration of CX-01, compared to 58% in patients treated with chemotherapy and low CX-01 concentration or 50% in patients that received chemotherapy alone (Kovacsovics et al, 2019).…”

Section: Soluble Factors Anchoring Lsc To the Stem Cell Niche And Thementioning

confidence: 95%

Leukemia Stem Cell Release From the Stem Cell Niche to Treat Acute Myeloid Leukemia

Villatoro

Konieczny

Cuminetti

et al. 2020

Front. Cell Dev. Biol.

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Acute myeloid leukemia (AML) is a heterogeneous, complex, and deadly disease, whose treatment has hardly evolved for decades and grounds on the use of intensive chemotherapy regimens. Chemotherapy helps reduce AML bulk, but promotes relapse in the long-run by selection of chemoresistant leukemia stem cells (LSC). These may diversify and result in progression to more aggressive forms of AML. In vivo models suggest that the bone marrow stem cell niche helps LSC stay dormant and protected from chemotherapy. Here, we summarize relevant changes in stem cell niche homing and adhesion of AML LSC vs. healthy hematopoietic stem cells, and provide an overview of clinical trials aiming at targeting these processes for AML treatment and future directions within this field. Promising results with various non-mutation-targeted novel therapies directed to LSC eradication via interference with their anchoring to the stem cell niche have encouraged ongoing or future advanced phase III clinical trials. In the coming years, we may see a shift in the focus of AML treatment to LSC-directed therapies if the prospect of improved cure rates holds true. In the future, AML treatment should lean toward personalized therapies using combinations of these compounds plus mutation-targeted agents and/or targeted delivery of chemotherapy, aiming at LSC eradication with reduced side effects.

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Combination of the low anticoagulant heparin CX-01 with chemotherapy for the treatment of acute myeloid leukemia

Cited by 47 publications

References 40 publications

Targeting High Mobility Group Box-1 (HMGB1) Promotes Cell Death in Myelodysplastic Syndrome

Targeting High Mobility Group Box-1 (HMGB1) Promotes Cell Death in Myelodysplastic Syndrome

The anti-cancer properties of heparin and its derivatives: a review and prospect

Leukemia Stem Cell Release From the Stem Cell Niche to Treat Acute Myeloid Leukemia

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