idelalisib and Lymphoma--B-Cell

In this paper, the authors provide a comprehensive overview of the activity and safety profile of idelalisib and other, newly developed PI3 K inhibitors in patients with indolent B-cell malignancies.. Idelalisib is a very potent anti-lymphoma agent in CLL and other NHL. However, there are some limitations of its broad clinical use according to some important side effects observed during treatment. Consequently, the development of new PI3 K inhibitors, which will be highly active and possess better safety profiles are warranted.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Phosphatidylinositol 3-Kinase; Protein Kinase Inhibitors; Purines; Quinazolinones; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Disease Management; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Incidence; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Severity of Illness Index

PI3K inhibitors are an important new therapeutic option for the treatment of relapsed and refractory B-cell lymphoid malignancies. Idelalisib is a PI3Kδ inhibitor that has been approved for the treatment of lymphoma and chronic lymphocytic leukemia in the relapsed/refractory setting, and several other PI3K inhibitors are being developed targeting other isoforms of the PI3K enzyme, which results in distinct toxicities and variable efficacy in the clinical setting. Areas covered: We provide a general overview of PI3K inhibitors, recommended applications, and the mechanism and management of toxicities. We further review trials, ongoing and completed, leading to the approval of idelalisib as well other PI3K inhibitors currently in development. Articles were obtained from PubMed, and abstracts were searched for the past 5 years from the websites for ASCO, ASH, EHA, and ICML/Lugano. Expert commentary: PI3K inhibitors provide an important and powerful pharmacologic tool in the armamentarium against hematologic malignancies, especially for relapsed/refractory B-cell lymphoid malignancies. Unique toxicities are associated with inhibition of different isoforms of the PI3K enzyme, as demonstrated with the infectious and autoimmune toxicities associated with the PI3Kδ inhibitor, idelalisib. Due to these unique toxicities, PI3K inhibitors should only be used in formally approved combinations and settings.

Topics: Antineoplastic Agents; Class I Phosphatidylinositol 3-Kinases; Enzyme Inhibitors; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Phosphoinositide-3 Kinase Inhibitors; Purines; Quinazolinones

Idelalisib, the first in-class phosphotidlyinositol 3-kinase delta (PI3Kδ) inhibitor, was approved by the US Food and Drug Administration in July 2014. It simultaneously received breakthrough therapy designation in combination with rituximab for the treatment of relapsed chronic lymphocytic leukemia (CLL) as well as accelerated approval as monotherapy for the treatment of relapsed follicular lymphoma and relapsed small lymphocytic lymphoma. In a pivotal phase III study of 220 patients with relapsed CLL, the overall response rate of patients who received rituximab plus idelalisib was 81%. The median progression-free survival (PFS) was 5 months with rituximab plus placebo group, but was not reached in the idelalisib arm. At 24 weeks, the PFS in patients receiving idelalisib was 93%. In a phase II trial of 125 patients with relapsed or refractory indolent non-Hodgkin lymphoma who received idelalisib 150 mg twice daily, the response rate was 57%. Complete response was seen in 6% of patients. The median duration of response was 12.5 months, and median PFS was 11 months. Idelalisib is a promising new therapy for relapsed indolent B-cell malignancies.

Topics: Animals; Antineoplastic Agents; Class I Phosphatidylinositol 3-Kinases; Clinical Trials as Topic; Drug Delivery Systems; Enzyme Inhibitors; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Phosphoinositide-3 Kinase Inhibitors; Purines; Quinazolinones

B-cell Non-Hodgkin lymphomas (B-NHLs) include a number of disease subtypes, each defined by the tempo of disease progression and the identity of the cancerous cell. Idelalisib is a potent, selective inhibitor of the delta isoform of phosphatidylinositol-3-kinase (PI3K), a lipid kinase whose over-activity in B-NHL drives disease progression. Idelalisib has demonstrated activity in indolent B-NHL (iB-NHL) and is approved for use as monotherapy in patients with follicular lymphoma and small lymphocytic lymphoma and in combination with rituximab in patients with chronic lymphocytic leukemia.. Herein we review the development and pharmacology of idelalisib, its safety and efficacy in clinical studies of iB-NHL, and its potential for inclusion in future applications in iB-NHL and in combination with other therapies.. Idelalisib adds to the growing arsenal of iB-NHL pharmacotherapeutics and to the progression of the field toward precision agents with good efficacy and reduced toxicities. Nevertheless, idelalisib carries important risks that require careful patient counseling and monitoring. The appropriate sequencing of idelalisib with other proven treatment options in addition to its potential for combination with established or novel drugs will be borne out in ongoing and planned investigations.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Lymphoma, B-Cell; Phosphoinositide-3 Kinase Inhibitors; Purines; Quinazolinones; Randomized Controlled Trials as Topic; Rituximab

Indolent non-Hodgkin's lymphoma (iNHL) describes a group of B-cell lymphomas with a long median survival and a relapsing-remitting clinical course. Although existing treatments are initially effective, patients often relapse, demonstrating decreasing efficacy with successive treatment courses. Alternative treatments are needed. PI3Kδ plays an essential, non-redundant role in B-cell receptor signaling critical to the pathogenesis of iNHL. It is expressed predominantly in hematopoietic cells, making PI3Kδ an attractive therapeutic target. Idelalisib is an oral PI3Kδ inhibitor approved in 2014 in the USA and the EU as monotherapy in relapsed follicular lymphoma or relapsed small lymphocytic lymphoma previously treated with two or more prior systemic therapies, or as part of combination therapy with rituximab in patients with chronic lymphocytic leukemia, for whom rituximab monotherapy would be considered appropriate due to the presence of comorbidities. Herein, we review the available data for idelalisib, with an emphasis on relapsed/refractory B-cell iNHL.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Interactions; Humans; Kidney; Liver; Lymphoma, B-Cell; Neoplasm Recurrence, Local; Phosphoinositide-3 Kinase Inhibitors; Purines; Quinazolinones; Treatment Outcome

Idelalisib (Zydelig(®)) is a highly specific small-molecule phosphatidylinositol-3-kinase (PI3Kδ) inhibitor that has been developed as an oral treatment for B cell haematological cancers.It has received its first approval in the US in July 2014 for the treatment of relapsed chronic lymphocytic leukaemia(CLL), relapsed follicular B-cell non-Hodgkin lymphoma(NHL) and relapsed small lymphocytic lymphoma (SLL) [corrected]. Idelalisib is under regulatory review in the EU-where it has received a positive opinion from the European Medicines Agency Committee for Medicinal Products for Human Use-and in clinical development for CLL in Australia and Canada. This article summarizes the milestones in the development of Idelalisib leading to this first approval for relapsed CLL, NHL and SLL.

Topics: Drug Approval; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Molecular Conformation; Purines; Quinazolinones; Small Molecule Libraries

Topics: Adult; Aged; Antineoplastic Agents; Female; Humans; Imidazoles; Indazoles; Lymphoma, B-Cell; Male; Middle Aged; Protein Kinase Inhibitors; Purines; Pyrazines; Pyrimidines; Quinazolinones

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Protein Kinase Inhibitors; Purines; Quinazolinones; Sulfonamides

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Humans; Lymphoma, B-Cell; Male; Middle Aged; Phosphoinositide-3 Kinase Inhibitors; Purines; Quinazolinones; Rituximab; Survival Rate

The infection risk in patients receiving ibrutinib, idelalisib or venetoclax for chronic lymphocytic leukaemia (CLL) or B-cell lymphoma treated outside of clinical trials is incompletely defined. We sought to identify the severe infection rate and associated risk factors in a 'real-world' cohort.. We conducted a retrospective cohort study of adult patients with CLL or lymphoma treated with ibrutinib, idelalisib or venetoclax.. Of 67 patients identified (ibrutinib n = 53, idelalisib n = 8 and venetoclax n = 6), 32 (48%) experienced severe infection. Severe infection occurred at a rate of 65 infections per 100 person-years, with a median of 17.8 months of therapy. Median time to first infection (IQR) was 5.4 months (1.4-15.9). Poor baseline Eastern Cooperative Oncology Group (ECOG) performance status and high Charlson Comorbidity Index (CCI) score associated with increased risk of severe infection [hazard ratios (95% CI) 1.57 (1.07-2.31, p = .018) and 1.3 (1.05-1.62, p = .016) respectively].. The severe infection rate for patients receiving ibrutinib, idelalisib or venetoclax for lymphoma and CLL exceeded those reported in clinical trials. Patients with poor ECOG or high CCI should be closely monitored for early signs of infection and prevention strategies actively pursued. Further prospective research is required to define optimal antimicrobial prophylaxis recommendations.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Retrospective Studies

We examined the efficacy and toxicity of the PI3Kδ inhibitor idelalisib in combination with rituximab salvage therapy in consecutively identified Swedish patients with chronic lymphocytic leukemia (CLL).. Thirty-seven patients with relapsed/refractory disease were included. The median number of prior lines of therapy was 3 (range 1-11); the median age was 69 years (range 50-89); 22% had Cumulative Illness Rating Scale (CIRS) >6 and 51% had del(17p)/TP53 mutation. The overall response rate was 65% (all but one was partial response [PR]). The median duration of therapy was 9.8 months (range 0.9-44.8). The median progression-free survival was 16.4 months (95% CI: 10.4-26.3) and median overall survival had not been reached (75% remained alive at 24 months of follow-up). The most common reason for cessation of therapy was colitis (n = 8, of which seven patients experienced grade ≥3 colitis). The most common serious adverse event was grade ≥3 infection, which occurred in 24 patients (65%).. Our real-world results suggest that idelalisib is an effective and relatively safe treatment for patients with advanced-stage CLL when no other therapies exist. Alternative dosing regimens and new PI3K inhibitors should be explored, particularly in patients who are double-refractory to inhibitors of BTK and Bcl-2.

Topics: Aged; Aged, 80 and over; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Middle Aged; Phosphatidylinositol 3-Kinases; Recurrence; Rituximab; Sweden

A series of 24 benzothiadiazine derivatives with structural novelty were designed, synthesized and biologically evaluated as PI3Kδ-selective inhibitors. As a consequence of the structure-activity relationship (SAR) study, compounds 63 and 71 were identified with single-digit nanomolar IC

Topics: Administration, Oral; Animals; Antineoplastic Agents; B-Lymphocytes; Benzothiadiazines; Cell Line, Tumor; Cell Proliferation; Class I Phosphatidylinositol 3-Kinases; Drug Design; Lymphoma, B-Cell; Molecular Docking Simulation; Protein Kinase Inhibitors; Rats, Sprague-Dawley

Topics: Allografts; Animals; B-Lymphocytes; Epstein-Barr Virus Infections; Female; Graft Rejection; Graft Survival; Heart Transplantation; Heterocyclic Compounds, 3-Ring; Humans; Inhibitory Concentration 50; Lymphoma, B-Cell; Lymphoproliferative Disorders; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Neoplasm Transplantation; Organ Transplantation; Phosphoinositide-3 Kinase Inhibitors; Postoperative Complications; Proto-Oncogene Proteins c-akt; Purines; Quinazolinones; Sirolimus; TOR Serine-Threonine Kinases

The PI 3-kinases (PI3K) are essential mediators of chemokine receptor signaling necessary for migration of chronic lymphocytic leukemia (CLL) cells and their interaction with tissue-resident stromal cells. While the PI3Kδ-specific inhibitor idelalisib shows efficacy in treatment of CLL and other B cell malignancies, the function of PI3Kγ has not been extensively studied in B cells. Here, we assess whether PI3Kγ has non-redundant functions in CLL migration and adhesion to stromal cells. We observed that pharmaceutical PI3Kγ inhibition with CZC24832 significantly impaired CLL cell migration, while dual PI3Kδ/γ inhibitor duvelisib had a greater impact than single isoform-selective inhibitors. Knockdown of PI3Kγ reduced migration of CLL cells and cell lines. Expression of the PI3Kγ subunits increased in CLL cells in response to CD40L/IL-4, whereas BCR cross-linking had no effect. Overexpression of PI3Kγ subunits enhanced cell migration in response to SDF1α/CXCL12, with the strongest effect observed within ZAP70 + CLL samples. Microscopic tracking of cell migration within chemokine gradients revealed that PI3Kγ functions in gradient sensing and impacts cell morphology and F-actin polarization. PI3Kγ inhibition also reduced CLL adhesion to stromal cells to a similar extent as idelalisib. These findings provide the first evidence that PI3Kγ has unique functions in malignant B cells.

Topics: Antineoplastic Agents; B-Lymphocytes; CD40 Ligand; Cell Adhesion; Cell Movement; Cell Survival; Chemokines; Chemotaxis; Class I Phosphatidylinositol 3-Kinases; Class Ib Phosphatidylinositol 3-Kinase; Cytoskeleton; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Immunoglobulin Heavy Chains; Interleukin-4; Leukemia, B-Cell; Lymphoma, B-Cell; Mesenchymal Stem Cells; Mutation; Phosphoinositide-3 Kinase Inhibitors; Purines; Quinazolinones; ZAP-70 Protein-Tyrosine Kinase

Idelalisib is approved for the treatment of relapsed chronic lymphocytic leukemia together with Rituximab and for monotherapy of follicular B-cell non-Hodgkin's lymphoma and small lymphocytic lymphoma. It is a potent and selective phosphatidylinositol 3-kinase-δ (PI3K-δ) inhibitor. PI3K-δ primarily is expressed in B-cells and prevents effectively proliferation in malignant B-cells.. We provide a detailed report on treatment history and photo documentation of acute adverse effects of radiation therapy with simultaneous Idelalisib medication in one case of B-CLL. Radiosensitivity tests were performed for the index patient under Idelalisib and after the addition of Idelalisib to healthy individuals' blood. Radiosensitivity in human lymphocytes was analyzed with a three color in situ hybridization assay. Primary skin fibroblasts were studied after a treatment with Idelalisib for apoptosis, necrosis and cell cycle using flow cytometry. DNA double-strand break repair was analyzed by γH2AX immunostaining.. The index patient presented a strong grade 2 radiodermatitis and grade 3 mucositis after irradiation with 20 Gy and a simultaneous intake of Idelalisib. Irradiations without Idelalisib medication were well tolerated and resulted in not more than grade 1 radiodermatitis. The index patient under Idelalisib had a radiosensitivity of 0.62 B/M which is in the range of clearly radiosensitive patients. A combined treatment of lymphocytes with 2 Gy and 10 nmol/l Idelalisib showed a tendency to an increased radiosensitivity. We found a clear increase of apoptosis as a result of the combined treatment in the Idelalisib dose range of 1 to 100 nmol/l compared to solely irradiated cells or solely Idelalisib treated cells (p = 0.05).. A combined Idelalisib radiotherapy treatment has an increased risk of side effects. However, combined therapy seems to be feasible when patients are monitored closely.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cells, Cultured; Fibroblasts; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytes; Lymphoma, B-Cell; Male; Mucositis; Prognosis; Purines; Quinazolinones; Radiation Tolerance; Radiotherapy; Rituximab

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; B-Lymphocytes; Cell Death; Cell Line; Humans; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Signal Transduction

Lymphomas are among the most common human cancers and represent the cause of death for still too many patients. The B-cell receptor with its downstream signaling pathways represents an important therapeutic target for B-cell lymphomas. Here, we evaluated the activity of the MEK1/2 inhibitor pimasertib as single agent and in combination with other targeted drugs in lymphoma preclinical models.. Cell lines derived mature B-cell lymphomas were exposed to increasing doses of pimasertib alone. Immunoblotting and gene expression profiling were performed. Combination of pimasertib with idelalisib or ibrutinib was assessed.. Pimasertib as single agent exerted a dose-dependent antitumor activity across a panel of 23 lymphoma cell lines, although at concentrations higher than reported for solid tumors. Strong synergism was observed with pimasertib combined with the PI3K inhibitor idelalisib and the BTK inhibitor ibrutinib in cell lines derived from diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma. The data were confirmed in an in vivo experiment treating DLBCL xenografts with pimasertib and ibrutinib.. The data presented here provide the basis for further investigation of regimens including pimasertib in relapsed and refractory lymphomas.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, B-Cell; MAP Kinase Kinase Kinases; Mice; Molecular Targeted Therapy; Niacinamide; Piperidines; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Signal Transduction; Xenograft Model Antitumor Assays

The novel Bruton tyrosine kinase inhibitor ibrutinib and phosphatidyl-4-5-biphosphate 3-kinase-δ inhibitor idelalisib are promising drugs for the treatment of chronic lymphocytic leukemia and B-cell non-Hodgkin lymphoma, either alone or in combination with anti-CD20 antibodies. We investigated the possible positive or negative impact of these drugs on all known mechanisms of action of both type I and type II anti-CD20 antibodies. Pretreatment with ibrutinib for 1 hour did not increase direct cell death of cell lines or chronic lymphocytic leukemia samples mediated by anti-CD20 antibodies. Pre-treatment with ibrutinib did not inhibit complement activation or complement-mediated lysis. In contrast, ibrutinib strongly inhibited all cell-mediated mechanisms induced by anti-CD20 antibodies rituximab, ofatumumab or obinutuzumab, either in purified systems or whole blood assays. Activation of natural killer cells, and antibody-dependent cellular cytotoxicity by these cells, as well as phagocytosis by macrophages or neutrophils were inhibited by ibrutinib with a half maximal effective concentration of 0.3-3 μM. Analysis of anti-CD20 mediated activation of natural killer cells isolated from patients on continued oral ibrutinib treatment suggested that repeated drug dosing inhibits these cells in vivo. Finally we show that the phosphatidyl-4-5-biphosphate 3-kinase-δ inhibitor idelalisib similarly inhibited the immune cell-mediated mechanisms induced by anti-CD20 antibodies, although the effects of this drug at 10 μM were weaker than those observed with ibrutinib at the same concentration. We conclude that the design of combined treatment schedules of anti-CD20 antibodies with these kinase inhibitors should consider the multiple negative interactions between these two classes of drugs.

Topics: Adenine; Antibodies, Monoclonal; Antibody-Dependent Cell Cytotoxicity; Antigens, CD20; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Case-Control Studies; Cell Proliferation; Cells, Cultured; Complement Activation; Flow Cytometry; Fluorescent Antibody Technique; Humans; Killer Cells, Natural; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Macrophages; Neutrophils; Phagocytosis; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones

Topics: Animals; Antineoplastic Agents; B-Lymphocytes; Chemokine CCL3; Class I Phosphatidylinositol 3-Kinases; Clinical Trials as Topic; Diarrhea; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Mice; Molecular Targeted Therapy; Mutation; Neoplasm Proteins; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Purines; Quinazolinones; Signal Transduction; Treatment Outcome; Tumor Microenvironment

Previously, we showed that inhibition of the protein kinase C β (PKCβ)/AKT pathway augments engagement of the histone deacetylase inhibitor (HDI)-induced apoptosis in lymphoma cells. In the present study, we investigated the cytotoxicity and mechanisms of cell death induced by the delta isoform-specific phosphatidylinositide 3-kinase (PI3K) inhibitor, GS-1101, in combination with the HDI, panobinostat (LBH589) and suberoylanilide hydroxamic acid (SAHA). Lymphoma cell lines, primary non-Hodgkin Lymphoma (NHL) and chronic lymphocytic leukaemia (CLL) cells were simultaneously treated with the HDI, LBH589 and GS-1101. An interaction of the LBH589/GS-1101 combination was formally examined by using various concentrations of LBH589 and GS-1101. Combined treatment resulted in a synergistic inhibition of proliferation and showed synergistic effect on apoptotic induction in all tested cell lines and primary NHL and CLL cells. This study indicates that interference with PI3K signalling dramatically increases HDI-mediated apoptosis in malignant haematopoietic cells, possibly through both AKT-dependent or AKT- independent mechanisms. Moreover, the increase in HDI-related apoptosis observed in PI3K inhibitor-treated cells appears to be related to the disruption of the extracellular signal-regulated kinase (ERK) signalling pathway. This study provides a strong rational for testing the combination of PI3K inhibitors and HDI in the clinic.

Topics: Antineoplastic Agents; Apoptosis; Caspases; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Inhibitory Concentration 50; Lymphoma, B-Cell; Models, Biological; Panobinostat; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Purines; Quinazolinones; Signal Transduction

Phosphatidylinositol-3-kinase p110δ serves as a central integration point for signaling from cell surface receptors known to promote malignant B-cell proliferation and survival. This provides a rationale for the development of small molecule inhibitors that selectively target p110δ as a treatment approach for patients with B-cell malignancies. We thus identified 5-fluoro-3-phenyl-2-[(S)-1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one (CAL-101), a highly selective and potent p110δ small molecule inhibitor (half-maximal effective concentration [EC(50)] = 8nM). Using tumor cell lines and primary patient samples representing multiple B-cell malignancies, we have demonstrated that constitutive phosphatidylinositol-3-kinase pathway activation is p110δ-dependent. CAL-101 blocked constitutive phosphatidylinositol-3-kinase signaling, resulting in decreased phosphorylation of Akt and other downstream effectors, an increase in poly(ADP-ribose) polymerase and caspase cleavage and an induction of apoptosis. These effects have been observed across a broad range of immature and mature B-cell malignancies, thereby providing a rationale for the ongoing clinical evaluation of CAL-101.

Topics: Animals; Antineoplastic Agents; Blotting, Western; Cell Line, Tumor; Cell Separation; Cell Survival; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Humans; Leukemia, B-Cell; Lymphoma, B-Cell; Mice; Mice, Inbred C57BL; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Purines; Quinazolinones; Signal Transduction