pci-32765 and fostamatinib

The development of targeted treatment of chronic lymphocytic leukaemia (CLL) is changing the prognostic outlook for CLL patients. The B-cell antigen receptor pathway is identified as pivotal for CLL pathogenesis and CLL cell proliferation. Inhibition of this pathway by ibrutinib (Bruton's tyrosin kinase inhibition) and idelalisib (phosphatidylinositol 3-kinase inhibition) has recently shown impressive clinical results, also for CLL patients with relapsed/refractory disease and unfavourable prognostic markers. Apoptosis induction by inhibition of BCL2 with ABT-199 is reported with likewise promising clinical results.

Topics: Adenine; Aminopyridines; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Morpholines; Oxazines; Piperidines; Purines; Pyrazoles; Pyridines; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Signal Transduction; Sulfonamides

B-cell receptor (BCR) signaling is a central pathologic mechanism in B-cell malignancies, including chronic lymphocytic leukemia (CLL), in which it promotes leukemia cell survival and proliferation, and modulates CLL cell migration and tissue homing. BCR signaling now can be targeted with new, small molecule inhibitors of the spleen tyrosine kinase (Syk), Bruton's tyrosine kinase (Btk), or phosphoinositide 3'-kinase (PI3K) isoform p110δ (PI3Kδ), which have recently entered the clinical stage and show promising results in patients with CLL. During the first weeks of therapy, these agents characteristically induce rapid resolution of lymphadenopathy and organomegaly, accompanied by a transient surge in lymphocyte counts due to "mobilization" of tissue-resident CLL cells into the blood. Then, often after months of continuous therapy, a major proportion of patients achieve remissions. This article reviews key biologic aspects of BCR-associated kinases in CLL and other B cell neoplasias, and develops perspectives for future development of this exciting new class of kinase inhibitors.

Topics: Adenine; Aminopyridines; Antineoplastic Agents; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Morpholines; Oxazines; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyridines; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Risk Factors; Signal Transduction

Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells that depend on host factors in the tissue microenvironment for survival and proliferation. In vitro, CLL cells rapidly undergo apoptosis unless microenvironmental factors are provided that support their survival. Signaling pathways activated in the microenvironment in vivo include the B-cell receptor (BCR) and NF-κB pathways. Thus, CLL is a disease "addicted to the host" and is dependent on pathways that promote normal B-cell development, expansion, and survival; this is particularly true in the case of the BCR signaling cascade. Small-molecule inhibitors of kinases that are essential for BCR signal transduction abrogate the stimulating effects of the microenvironment on CLL cells. The orally administered tyrosine kinase inhibitors fostamatinib and ibrutinib and the phosphatidylinositol 3-kinase inhibitor GS-1101 have induced impressive responses in relapsed and refractory CLL patients, mostly with moderate side effects. Reductions in lymphadenopathy and splenomegaly are seen within weeks and are frequently accompanied by a transient rise in absolute lymphocyte count that is asymptomatic and probably the result of changes in CLL cell trafficking. This review discusses the biologic basis for kinase inhibitors as targeted therapy of CLL and summarizes the exciting early clinical experience with these agents.

Topics: Adenine; Aminopyridines; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Models, Biological; Morpholines; Oxazines; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyridines; Pyrimidines; Receptors, Antigen, B-Cell; Signal Transduction

Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells that depend on host factors in the tissue microenvironment for survival and proliferation. In vitro, CLL cells rapidly undergo apoptosis unless microenvironmental factors are provided that support their survival. Signaling pathways activated in the microenvironment in vivo include the B-cell receptor (BCR) and NF-κB pathways. Thus, CLL is a disease "addicted to the host" and is dependent on pathways that promote normal B-cell development, expansion, and survival; this is particularly true in the case of the BCR signaling cascade. Small-molecule inhibitors of kinases that are essential for BCR signal transduction abrogate the stimulating effects of the microenvironment on CLL cells. The orally administered tyrosine kinase inhibitors fostamatinib and ibrutinib and the phosphatidylinositol 3-kinase inhibitor GS-1101 have induced impressive responses in relapsed and refractory CLL patients, mostly with moderate side effects. Reductions in lymphadenopathy and splenomegaly are seen within weeks and are frequently accompanied by a transient rise in absolute lymphocyte count that is asymptomatic and probably the result of changes in CLL cell trafficking. This review discusses the biologic basis for kinase inhibitors as targeted therapy of CLL and summarizes the exciting early clinical experience with these agents.

Topics: Adenine; Aminopyridines; Antineoplastic Agents; Clinical Trials as Topic; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Count; Medical Oncology; Morpholines; Mutation; NF-kappa B; Oxazines; Phosphatidylinositol 3-Kinases; Piperidines; Purines; Pyrazoles; Pyridines; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Signal Transduction; src-Family Kinases

Approximately one third of Diffuse Large B cell Lymphomas (DLBCL) are refractory or relapse. Novel therapeutic approaches under scrutiny include inhibitors of B-cell receptor (BCR) signaling. Protein kinase CK2 propels survival, proliferation and stress response in solid and hematologic malignancies and promotes a "non-oncogene addiction" phenotype. Whether this kinase regulates BCR signaling, being a suitable pharmacological target in DLBCL, is unknown.. The objective was to establish if CK2 controls DLBCL cell survival and the BCR signaling, to check if the combination of CK2 inhibitor CX-4945 and BCR blockers Ibrutinib and Fostamatinib is more effectively cytotoxic for DLBCL cells than the single agents and to survey the changes in signaling molecules downstream BCR upon CK2 inhibition.. A panel of GC and ABC DLBCL cells was treated with CX-4945 and Fostamatinib or Ibrutinib. BCR signaling was assayed by intracellular Ca++ measurement and looking at the phosphorylation of signaling molecules. The effects on cell survival were assessed by flow cytometry, western blot and MTT assays.. CK2 inhibition with CX-4945 causes DLBCL cell death. CX-4945 impaired AKT phosphorylation and intracellular Ca++ mobilization upon BCR engagement. The CK2 inhibitor acted synergistically with either the SYK inhibitor Fostamatinib or the BTK inhibitor Ibrutinib in inducing DLBCL cell death. CX-4945 was equally effective in GC and ABC DLBCL subtypes as well as in "double hit" DLBCL cell lines.. These findings suggest a role for CK2 downstream of the BCR in controlling survival pathways crucial for cell growth of different DLBCL subtypes. Also, the use of CX-4945 in combination with BCR signaling blockers could represent a novel rational therapeutic approach in the DLBCL.

Topics: Adenine; Aminopyridines; Apoptosis; Casein Kinase II; Cell Proliferation; Drug Synergism; Humans; Lymphoma, Large B-Cell, Diffuse; Morpholines; Naphthyridines; Oxazines; Phenazines; Piperidines; Pyrazoles; Pyridines; Pyrimidines; Receptors, Antigen, B-Cell; Tumor Cells, Cultured

Several studies provide evidences for mantle cell lymphoma (MCL) cell survival relying on B-cell receptor (BCR)-mediated signalling pathways, whereas the nature of this activation is unknown. Significant progress in MCL treatment is achieved through therapies targeting BCR-associated kinases, i.e., Ibrutinib and Fostamatinib, inhibitors of BTK and SYK, respectively. Our study addresses survival signals emanating from the BCR or the tumour environment and how inhibiting BCR signalling effectors might impact these survival signals. We found that BTK was constitutively activated and that SYK phosphorylation was highly increased and sustained upon BCR activation of primary MCL cells. Moreover, MCL cells from leukaemic patients secreted high amount of IL-1β, IL-6, IL-8 and CCL5. Activation of the BCR induced (i) cell survival, (ii) STAT3 activation and (iii) increased autocrine secretion of IL-1β, IL-6, IL-8, CCL5, IL-10, TNFα and VEGF. Specific inhibition of BTK by Ibrutinib or SYK by Fostamatinib (R406) reversed these protective effects and decreased both basal and BCR-induced autocrine cytokine secretions associated with STAT3 phosphorylation. Interestingly, targeting BTK and SYK prevented and inhibited BCR-induced MCL cell adhesion to human bone marrow stromal cells (HMSCs) in short- and long-term co-culture. We demonstrated that BCR-induced survival relies on autocrine secretion of IL-1β, TNFα and CCL5 that might facilitate adhesion of MCL cells to HMSC. Treatment with Ibrutinib or Fostamatinib blocked the chemotactic signal thus increasing apoptosis.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Aminopyridines; Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Survival; Cells, Cultured; Coculture Techniques; Cytokines; Female; Gene Expression; Humans; Intracellular Signaling Peptides and Proteins; Lymphoma, Mantle-Cell; Male; Middle Aged; Morpholines; Oxazines; Phosphorylation; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyridines; Pyrimidines; Receptors, Antigen, B-Cell; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Syk Kinase; Tumor Cells, Cultured

BCR signaling pathway inhibitors such as ibrutinib, idelalisib, and fostamatinib (respective inhibitors of Bruton's tyrosine kinase, PI3Kδ, and spleen tyrosine kinase) represent a significant therapeutic advance in B cell malignancies, including chronic lymphocytic leukemia (CLL). These drugs are distinctive in increasing blood lymphocytes while simultaneously shrinking enlarged lymph nodes, suggesting anatomical redistribution of CLL cells from lymph nodes into the blood. However, the mechanisms underlying this phenomenon are incompletely understood. In this study, we showed that the egress receptor, sphingosine-1-phosphate (S1P) receptor 1 (S1PR1), was expressed at low levels in normal germinal centers and CLL lymph nodes in vivo but became upregulated on normal B cells and, to a variable and lesser extent, CLL cells following in vitro incubation in S1P-free medium. Spontaneous recovery of S1PR1 expression on normal B and CLL cells was prevented by BCR cross-linking, whereas treatment of CLL cells with idelalisib increased S1PR1 expression and migration toward S1P, the greatest increase occurring in cases with unmutated IgH V region genes. Intriguingly, ibrutinib and fostamatinib had no effect on S1PR1 expression or function. Conversely, chemokine-induced migration, which requires integrin activation and is essential for the entry of lymphocytes into lymph nodes as well as their retention, was blocked by ibrutinib and fostamatinib, but not idelalisib. In summary, our results suggest that different BCR signaling inhibitors redistribute CLL cells from lymph nodes into the blood through distinct mechanisms: idelalisib actively promotes egress by upregulating S1PR1, whereas fostamatinib and ibrutinib may reduce CLL cell entry and retention by suppressing chemokine-induced integrin activation.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aminopyridines; Antineoplastic Agents; B-Lymphocytes; Case-Control Studies; Cell Movement; Class I Phosphatidylinositol 3-Kinases; Gene Expression Regulation, Leukemic; Germinal Center; Human Umbilical Vein Endothelial Cells; Humans; Integrins; Intracellular Signaling Peptides and Proteins; Leukemia, Lymphocytic, Chronic, B-Cell; Lymph Nodes; Lysophospholipids; Morpholines; Oxazines; Piperidines; Primary Cell Culture; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyridines; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors; Syk Kinase