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Genevra Pillinger, Niamh V Loughran, Rachel E Piddock, Manar S Shafat, Lyubov Zaitseva, Amina Abdul-Aziz, Matthew J Lawes, Kristian M Bowles, Stuart A Rushworth
Phosphoinositide-3-kinase (PI3K) is an enzyme group, known to regulate key survival pathways in acute myeloid leukaemia (AML). It generates phosphatidylinositol-3,4,5-triphosphate, which provides a membrane docking site for protein kinaseB activation. PI3K catalytic p110 subunits are divided into 4 isoforms; α,β,δ and γ. The PI3Kδ isoform is always expressed in AML cells, whereas the frequency of PI3Kγ expression is highly variable. The functions of these individual catalytic enzymes have not been fully resolved in AML, therefore using the PI3K p110δ and p110γ-targeted inhibitor IPI-145 (duvelisib) and specific p110δ and p110γ shRNA, we analysed the role of these two p110 subunits in human AML blast survival...
June 28, 2016: Oncotarget
Carolyn Owen, Sarit Assouline, John Kuruvilla, Cassandra Uchida, Catherine Bellingham, Laurie Sehn
Chronic lymphocytic leukemia (CLL) is the most common adult lymphoproliferative disorder in Western countries. The current standard of care for CLL is chemoimmunotherapy, typically with fludarabine, cyclophosphamide, and rituximab (FCR). However, most patients with CLL are elderly with comorbidities and are unable to tolerate FCR. In order to choose the best treatment for each individual patient, physicians must balance efficacy with toxicity. In addition, most currently available treatments are ineffective in CLL patients with loss of TP53...
November 2015: Clinical Lymphoma, Myeloma & Leukemia
K Balakrishnan, M Peluso, M Fu, N Y Rosin, J A Burger, W G Wierda, M J Keating, K Faia, S O'Brien, J L Kutok, V Gandhi
The functional relevance of the B-cell receptor (BCR) and the evolution of protein kinases as therapeutic targets have recently shifted the paradigm for treatment of B-cell malignancies. Inhibition of p110δ with idelalisib has shown clinical activity in chronic lymphocytic leukemia (CLL). The dynamic interplay of isoforms p110δ and p110γ in leukocytes support the hypothesis that dual blockade may provide a therapeutic benefit. IPI-145, an oral inhibitor of p110δ and p110γ isoforms, sensitizes BCR-stimulated and/or stromal co-cultured primary CLL cells to apoptosis (median 20%, n=57; P<0...
September 2015: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Elisa Göckeritz, Susan Kerwien, Michael Baumann, Marion Wigger, Verena Vondey, Lars Neumann, Thomas Landwehr, Clemens M Wendtner, Christian Klein, Ningshu Liu, Michael Hallek, Lukas P Frenzel, Günter Krause
Pharmacological inhibition of phosphatiylinositide-3-kinase (PI3K)-mediated signaling holds great promise for treating chronic lymphocytic leukemia (CLL). Therefore we assessed three structurally related PI3K inhibitors targeting the PI3K-δ isoform for their ability to inhibit the survival of freshly isolated CLL cells. The purely PI3K-δ-selective inhibitor idelalisib was compared to copanlisib (BAY 80-6946) and duvelisib (IPI-145), with isoform target profiles that additionally include PI3K-α or PI3K-γ, respectively...
November 1, 2015: International Journal of Cancer. Journal International du Cancer
Annalisa Lonetti, Alessandra Cappellini, Antonino Maria Spartà, Francesca Chiarini, Francesca Buontempo, Camilla Evangelisti, Cecilia Evangelisti, Ester Orsini, James A McCubrey, Alberto Maria Martelli
Class I phosphatidylinositol 3-kinases (PI3Ks) are frequently activated in T-cell acute lymphoblastic leukemia (T-ALL), mainly due to the loss of PTEN function. Therefore, targeting PI3Ks is a promising innovative approach for T-ALL treatment, however at present no definitive evidence indicated which is the better therapeutic strategy between pan or selective isoform inhibition, as all the four catalytic subunits might participate in leukemogenesis. Here, we demonstrated that in both PTEN deleted and PTEN non deleted T-ALL cell lines, PI3K pan-inhibition exerted the highest cytotoxic effects when compared to both selective isoform inhibition or dual p110γ/δ inhibition...
April 30, 2015: Oncotarget
Fabiola Cervantes-Gomez, Betty Lamothe, Jennifer A Woyach, William G Wierda, Michael J Keating, Kumudha Balakrishnan, Varsha Gandhi
PURPOSE: Bruton's tyrosine kinase (BTK) is a critical enzyme in the B-cell receptor pathway and is inhibited by ibrutinib due to covalent binding to the kinase domain. Though ibrutinib results in impressive clinical activity in chronic lymphocytic leukemia (CLL), most patients achieve only partial remission due to residual disease. We performed a pharmacologic profiling of residual circulating CLL cells from patients receiving ibrutinib to identify optimal agents that could induce cell death of these lymphocytes...
August 15, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Anjali Varma Desai, Hassan El-Bakkar, Maher Abdul-Hay
Half of a century ago, physicians managing chronic lymphocytic leukemia (CLL) recognized some of its presenting features such as lymphocytosis, lymphadenopathy, and splenomegaly. Subsequently, an enhanced understanding of the disease mechanisms involved in CLL led to new, more targeted treatments. There is now a plethora of treatments available for CLL. In this review article we discuss in detail several of the novel agents that are being studied or approved for the treatment of CLL including: phosphatidylinositol 3-kinase inhibitors (idelalisib and IPI-145), Bruton tyrosine kinase inhibitors (ibrutinib), B cell lymphoma 2 inhibitors (ABT-263 and ABT-199), new anti-CD20 monoclonal antibodies (obinutuzumab), cyclin-dependent kinase inhibitors (flavopiridol and dinaciclib), immunomodulators (lenalidomide) and chimeric antigen receptor T-cell therapy...
June 2015: Clinical Lymphoma, Myeloma & Leukemia
Shuai Dong, Daphne Guinn, Jason A Dubovsky, Yiming Zhong, Amy Lehman, Jeffery Kutok, Jennifer A Woyach, John C Byrd, Amy J Johnson
Chronic lymphocytic leukemia (CLL) displays constitutive phosphatidylinositol 3-kinase (PI3K) activation resulting from aberrant regulation of B-cell receptor (BCR) signaling. Previous studies have shown that an oral PI3K p110δ inhibitor idelalisib exhibits promising activity in CLL. Here, we demonstrate that a dual PI3K p110δ and p110γ inhibitor, IPI-145, antagonizes BCR crosslinking activated prosurvival signals in primary CLL cells. IPI-145 causes direct killing in primary CLL cells in a dose- and time-dependent fashion, but does not generate direct cytotoxicity to normal B cells...
December 4, 2014: Blood
Emily Curran, Sonali M Smith
PURPOSE OF REVIEW: The phosphoinositide 3-kinase (PI3K) pathway, with downstream targets including Akt and mammalian target of rapamycin, has been implicated in numerous human cancers, including hematologic malignancies and lymphomas. The development and refinement of PI3K inhibitors directed toward this pathway show promising clinical efficacy. This review will discuss the emerging body of clinical data in lymphoid malignancies and present future directions for research utilizing these inhibitors...
September 2014: Current Opinion in Oncology
Steven T Rosen, Brian K Link, Nathan H Fowler
Mantle cell lymphoma is one of the most challenging hematologic malignancies, owing to an aggressive disease course, a high rate of relapse, and lack of standard of care. In the United States, mantle cell lymphoma accounts for approximately 6% of all newly diagnosed cases of non-Hodgkin lymphoma. Because most patients are initially diagnosed with advanced-stage disease, they are often symptomatic at presentation. Common features include widespread lymphadenopathy and splenomegaly, as well as bone marrow infiltration...
November 2013: Clinical Advances in Hematology & Oncology: H&O
(no author information available yet)
Results from a phase I study of Infinity Pharmaceuticals' IPI-145, which inhibits both δ and γ isoforms of phosphoinositide3-kinase, suggest the drug is safe and effective in patients with advanced chronic lymphocytic leukemia.
February 2014: Cancer Discovery
Julie E Chang, Brad S Kahl
The phosphatidylinositol 3-kinase (PI3K) pathway is being explored as a target of inhibition for B-cell lymphoproliferative disorders, with agents specific for inhibition of the PI3K-δ subunit showing significant clinical activity in chronic lymphocytic leukemia (CLL). Idelalisib (CAL-101, GS-1101) and IPI-145 (INK-1147) are novel oral PI3K-δ inhibitors in development, with rates of objective response of 40-60 % and nodal responses exceeding 70 % in relapsed and refractory CLL. High rates of response have been seen in high-risk CLL (i...
March 2014: Current Hematologic Malignancy Reports
Klaus Okkenhaug
In this issue of Chemistry & Biology, Winkler and colleagues describe the discovery and preclinical development of IPI-145, a new inhibitor of the phosphoinositide 3-kinase (PI3K) isoforms p110δ and p110γ that have entered clinical trials.
November 21, 2013: Chemistry & Biology
David L Boyle, Hae-Rim Kim, Katharyn Topolewski, Beatrix Bartok, Gary S Firestein
Phosphoinositide 3-kinases γ and δ (PI3Kγ and PI3Kδ) are expressed in rheumatoid arthritis (RA) synovium and regulate innate and adaptive immune responses. We determined the effect of a potent PI3Kδ,γ inhibitor, IPI-145, in two preclinical models of RA. IPI-145 was administered orally in rat adjuvant-induced arthritis (AA) and intraperitoneally in mouse collagen-induced arthritis (CIA). Efficacy was assessed by paw swelling, clinical scores, histopathology and radiography, and microcomputed tomography scanning...
February 2014: Journal of Pharmacology and Experimental Therapeutics
David G Winkler, Kerrie L Faia, Jonathan P DiNitto, Janid A Ali, Kerry F White, Erin E Brophy, Melissa M Pink, Jennifer L Proctor, Jennifer Lussier, Christian M Martin, Jennifer G Hoyt, Bonnie Tillotson, Erin L Murphy, Alice R Lim, Brian D Thomas, John R Macdougall, Pingda Ren, Yi Liu, Lian-Sheng Li, Katti A Jessen, Christian C Fritz, Joi L Dunbar, James R Porter, Christian Rommel, Vito J Palombella, Paul S Changelian, Jeffery L Kutok
Phosphoinositide-3 kinase (PI3K)-δ and PI3K-γ are preferentially expressed in immune cells, and inhibitors targeting these isoforms are hypothesized to have anti-inflammatory activity by affecting the adaptive and innate immune response. We report on a potent oral PI3K-δ and PI3K-γ inhibitor (IPI-145) and characterize this compound in biochemical, cellular, and in vivo assays. These studies demonstrate that IPI-145 exerts profound effects on adaptive and innate immunity by inhibiting B and T cell proliferation, blocking neutrophil migration, and inhibiting basophil activation...
November 21, 2013: Chemistry & Biology
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