Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia

Friedberg, Jonathan W.; Sharman, Jeff P.; Sweetenham, John W.; Johnston, Patrick B.; Vose, Julie M.; LaCasce, Ann S.; Schaefer-Cutillo, Julia; Vos, Sven de; Sinha, Rajni; Leonard, John P.; Cripe, Larry D.; Gregory, Stephanie A.; Sterba, Michael P.; Lowe, Ann M.; Levy, Ronald; Shipp, Margaret A.

doi:10.1182/blood-2009-08-236471

Cited by 669 publications

(577 citation statements)

References 44 publications

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“…Recent data indicate that T-cell non-Hodgkin's lymphoma cell proliferation is dependent on Syk, 44 and that many of the same signaling pathways that are active in malignant lymphoma cells where Syk inhibitors are already applied clinically 45 are also relevant for the activation of non-malignant lymphocytes. To address the mechanism for the potent protective in vivo effects against Tc-mediated GvHD, we first turned toward Tcs and observed reduced proliferative allo-responses in vitro that were consistent with the reduced expansion of Tc luc documented in vivo.…”

Section: Discussionmentioning

confidence: 99%

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Spleen tyrosine kinase (Syk) is a potent target for GvHD prevention at different cellular levels

Leonhardt

Zirlik²,

Buchner

et al. 2012

Leukemia

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Section: Discussionmentioning

confidence: 99%

“…On the basis of the antineoplastic effects of Fostamatinib in non-Hodgkin lymphomas, 44,45 Syk inhibition may even be synergistic with allo responses and render leukemias more susceptible to Tc-mediated cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Spleen tyrosine kinase (Syk) is a potent target for GvHD prevention at different cellular levels

Leonhardt

Zirlik²,

Buchner

et al. 2012

Leukemia

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“…Work by Krysov and colleagues (7) has shown that the BCR expressed on CLL cells, particularly from patients with UM-CLL, shows features that are associated with continuous in vivo exposure to antigen, whereas others have shown that such continuous BCR-stimulation is reflected in the pattern of gene expression observed in freshly isolated cells (8). Taken together, these observations suggest that targeting this continuous BCR signaling may show therapeutic benefit in patients with CLL with progressive disease, and new drugs that inhibit particular elements within the BCR signaling pathway such as phosphoinositide 3-kinase d (PI3Kd), spleen tyrosine kinase (Syk), and Bruton's tyrosine kinase (BTK) seem to show promise (9)(10)(11). However, the concentrations of these compounds needed to observe an effect in treated cells are disproportionate to those needed to inhibit the specific kinases they target.…”

Section: Introductionmentioning

confidence: 98%

LCK Is an Important Mediator of B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia Cells

Talab

Allen

Thompson

et al. 2013

Molecular Cancer Research

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B-cell receptor (BCR) signals promote survival of chronic lymphocytic leukemia (CLL) cells, and it is believed that overexpressed and constitutively active Lyn mediates this signaling. Here, we show that CLL cells express lymphocyte-specific protein tyrosine kinase (LCK) and that inhibition of this Src family tyrosine kinase with the specific inhibitor [4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[3,2-d]pyrimidin-7-yl-cyclopentane (Lck-i)], or reduction of its expression with siRNA, blocks the induction of CD79a, Syk, inhibitor of IkB kinase (IKK), Akt, and extracellular signal-regulated kinase (ERK) phosphorylation by BCR cross-linking in these cells. Furthermore, we show that CLL cells with high levels of LCK expression have higher levels of BCR-mediated IKK, Akt, and ERK phosphorylation as well as cell survival than CLL cells with low levels of LCK expression. We also show that treatment of CLL cells with Lck-i inhibits BCR cross-linking-induced cell survival. Taken together, these data show a major role for LCK in proximal and distal BCR-mediated signaling in CLL cells and suggest that LCK expression is important in the pathogenesis of this disease. On a clinical level, these studies advocate the use of specific LCK inhibitors in the treatment of progressive CLL. Mol Cancer Res; 11(5); 541-54. Ó2013 AACR.

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“…Antigenic stimulation is channeled into the cytoplasm of CLL via the BCR, which is a multimolecular complex comprised of surface IgM and associated components within the membrane plane, including CD19, CD21 and CD81, and associated cytoplasmic accessory/signaling molecules, including Syk, and in some patients ZAP70 (3,6,7). Owing to the prime importance of the BCR in the physiology of malignant B cells, the expression of some of its components and associated molecules serves as prognostic factors (e.g., ZAP70) (8) or as therapeutic targets (e.g., CD20, Syk, Btk) in CLL and other lymphoproliferative disorders (LPD) (9,10). Growing evidence supports the concept that intraclonal CLL cell diversity plays a role in the disease biology and eventual clinical outcome (11)(12)(13).…”

mentioning

confidence: 99%

Divergence in CD19-Mediated Signaling Unfolds Intraclonal Diversity in Chronic Lymphocytic Leukemia, Which Correlates with Disease Progression

Herishanu

Kay

Dezorella

et al. 2013

The Journal of Immunology

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Emerging data on intraclonal diversity imply that this phenomenon may play a role in the clinical outcome of patients with chronic lymphocytic leukemia (CLL), where subsets of the CLL clone responding more robustly to external stimuli may gain a growth and survival advantage. In this study, we report intraclonal diversity resolved by responses to CD19 engagement in CLL cells, which can be classified into CD19-responsive (CD19-R) and -nonresponive subpopulations. Engagement of CD19 by anti-CD19 Ab rapidly induced cellular aggregation in the CD19-R CLL cells. The CD19-R CLL cells expressed higher surface levels of CD19 and c-myc mRNA, exhibited distinct morphological features, and were preferentially abolished in rituximab-treated patients. Both subpopulations reacted to sIgM stimulation in a similar manner and exhibited similar levels of Akt and Erk phosphorylation, pointing to functional signaling divergence within the BCR. CD19 unresponsiveness was partially reversible, where nonresponding CD19 cells spontaneously recover their signaling capacity following incubation in vitro, pointing to possible in vivo CD19–signaling attenuating mechanisms. This concept was supported by the lower CD19-R occurrence in bone marrow–derived samples compared with cells derived from the peripheral blood of the same patients. CLL patients with >15.25% of the CD19-R cell fraction had a shorter median time to treatment compared with patients with <15.25% of CD19-R cell fraction. In conclusion, divergence in CD19-mediated signaling unfolds both interpatient and intraclonal diversity in CLL. This signaling diversity is associated with physiological implications, including the location of the cells, their responses to anti-CLL therapeutics, and disease progression.

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Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia

Cited by 669 publications

References 44 publications

Spleen tyrosine kinase (Syk) is a potent target for GvHD prevention at different cellular levels

Spleen tyrosine kinase (Syk) is a potent target for GvHD prevention at different cellular levels

LCK Is an Important Mediator of B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia Cells

Divergence in CD19-Mediated Signaling Unfolds Intraclonal Diversity in Chronic Lymphocytic Leukemia, Which Correlates with Disease Progression

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