Effects of the small-molecule inhibitor of integrin α4, TBC3486, on pre-B-ALL cells

Hsieh, Yao-Te; Gang, Eun Ji; Shishido, Stephanie N.; Kim, H N; Pham, Jennifer; Khazal, Sajad; Osborne, A; Esguerra, Zitadel Anne; Kwok, Eric S. C.; Jang, Jung Yun; Bönig, Halvard-Björn; Biediger, Ronald J.; Vanderslice, Peter; Kim, Y M

doi:10.1038/leu.2014.182

Cited by 32 publications

(35 citation statements)

References 10 publications

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“…We and others have demonstrated the potential of CD49d-targeting treatments as supplementation for cytoreductive chemotherapy in acute leukemia. The proposed mechanism of action is disruption of adhesive interactions of leukemia cells with BM stroma, stroma providing survival cues, adhesive interactions signaling negative cell cycle activity, and de-adhesion also resulting in physically better exposure to chemotherapy drugs, in aggregate resulting in more effective leukemia cell killing by chemotherapy drugs[ 3 , 5 , 10 , 11 ]. While anti-functional antibodies for CD49d targeting are available, certain disadvantages are associated with these.…”

Section: Discussionmentioning

confidence: 99%

Effects of CD49d-targeted antisense-oligonucleotide on α4 integrin expression and function of acute lymphoblastic leukemia cells: Results of in vitro and in vivo studies

et al. 2017

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We recently demonstrated the effectiveness of blocking CD49d with anti-functional antibodies or small molecule inhibitors as a rational targeted approach to the treatment of acute leukemia in combination with chemotherapy. Antisense oligonucleotide promises to be no less specific than antibodies and inhibitors, but more interesting for pharmacokinetics and pharmacodynamics. We addressed this using the published CD49d antisense drug ATL1102. In vitro, we incubated/nucleofected the ALL cell line Kasumi-2 with ATL1102. In vivo, immunodeficient hosts were engrafted with primary ALL cells and treated with ATL1102. Changes in expression of CD49d mRNA and CD49d protein, and of cooperating gene products, including ß1 integrin and CXCR4, as well as survival in the mouse experiments were quantified. We observed dose-dependent down-regulation of CD49d mRNA and protein levels and its partner integrin ß1 cell surface protein level and, up-regulation of CXCR4 surface expression. The suppression was more pronounced after nucleofection than after incubation, where down-regulation was significant only at the higher doses. In vivo effects of ATL1102 were not sufficient to translate into “clinical” benefit in the leukemia model. In summary, antisense oligonucleotides are successful tools for specifically modulating gene expression but sufficient delivery to down-regulate CD49d in vivo may be difficult to achieve.

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Section: Discussionmentioning

confidence: 99%

Effects of CD49d-targeted antisense-oligonucleotide on α4 integrin expression and function of acute lymphoblastic leukemia cells: Results of in vitro and in vivo studies

et al. 2017

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“…This interaction can be blocked with the FDA-approved monoclonal antibody Natalizumab , which targets both α4 and αE integrins and is currently used for the treatment of relapsing multiple sclerosis and inflammatory bowel disease. A small molecule specifically targeting VCAM-1 has recently been developed (Hsieh et al, 2014), and would be the ideal drug for testing in myeloid malignancies.…”

Section: Uncoupling Leukemic Cells From Their Protective Nichesmentioning

confidence: 99%

Normal and Leukemic Stem Cell Niches: Insights and Therapeutic Opportunities

2015

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Hematopoietic stem cells (HSC) rely on instructive cues from the bone marrow (BM) niche to maintain their quiescence and adapt blood production to the organism’s needs. Alterations in the BM niche are commonly observed in blood malignancies and directly contribute to the aberrant function of disease-initiating leukemic stem cells (LSC). Here, we review recent insights into the cellular and molecular determinants of the normal HSC niche and describe how genetic changes in stromal cells and leukemia-induced BM niche remodeling contribute to blood malignancies. Moreover, we discuss how these findings can be applied to non cell-autonomous therapies targeting the LSC niche.

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“…Therefore, it was not surprising that high VLA-4 expression in children with relapsed B-ALL was associated with unfavorable prognosis (19). Thus, blocking of VLA-4/VCAM-1 binding by a humanized antibody targeting VLA-4 (natalizumab) or a ligand-mimetic small molecule inhibitor of integrin α4 (TBC3486) not only sensitized B-ALL cells to chemotherapy, but also prolonged survival in leukemia bearing mice in preclinical studies (20,21). …”

Section: Cams Involved In Chemoprotection In Allmentioning

confidence: 99%

Eviction from the sanctuary: Development of targeted therapy against cell adhesion molecules in acute lymphoblastic leukemia

Barwe

Quagliano

Gopalakrishnapillai

2017

Seminars in Oncology

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Acute lymphoblastic leukemia (ALL) is a malignant hematological disease afflicting hematopoiesis in the bone marrow. While 80-90% of patients diagnosed with ALL will achieve complete remission at some point during treatment, ALL is associated with high relapse rate, with the 5-year overall survival rate of 68%. The initial remission failure and the high rate of relapse can be attributed to intrinsic chemoprotective mechanisms that allow persistence of ALL cells despite therapy. These mechanisms are mediated, at least in part, through the engagement of cell adhesion molecules (CAMs) within the bone marrow microenvironment. This review assembles CAMs implicated in protection of leukemic cells from chemotherapy. Such studies are limited in ALL. Therefore, CAMs that are associated with poor outcomes or are over-expressed in ALL and have been shown to be involved in chemoprotection in other hematological cancers are also included. It is likely that these molecules play parallel roles in ALL because the CAMs identified to be a factor in ALL chemoresistance also work similarly in other hematological malignancies. We review the signaling mechanisms activated by the engagement of CAMs that provide protection from chemotherapy. Development of targeted therapies against CAMs could improve outcome and raise the overall cure rate in ALL.

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Effects of the small-molecule inhibitor of integrin α4, TBC3486, on pre-B-ALL cells

Cited by 32 publications

References 10 publications

Effects of CD49d-targeted antisense-oligonucleotide on α4 integrin expression and function of acute lymphoblastic leukemia cells: Results of in vitro and in vivo studies

Effects of CD49d-targeted antisense-oligonucleotide on α4 integrin expression and function of acute lymphoblastic leukemia cells: Results of in vitro and in vivo studies

Normal and Leukemic Stem Cell Niches: Insights and Therapeutic Opportunities

Eviction from the sanctuary: Development of targeted therapy against cell adhesion molecules in acute lymphoblastic leukemia

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