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  1. Article ; Online: B cell signalling pathways-New targets for precision medicine in chronic lymphocytic leukaemia.

    Skånland, Sigrid S / Karlsen, Linda / Taskén, Kjetil

    Scandinavian journal of immunology

    2020  Volume 92, Issue 5, Page(s) e12931

    Abstract: The B cell receptor (BCR) is a master regulator of B cells, controlling cellular processes such as proliferation, migration and survival. Cell signalling downstream of the BCR is aberrantly activated in the B cell malignancy chronic lymphocytic leukaemia ...

    Abstract The B cell receptor (BCR) is a master regulator of B cells, controlling cellular processes such as proliferation, migration and survival. Cell signalling downstream of the BCR is aberrantly activated in the B cell malignancy chronic lymphocytic leukaemia (CLL), supporting the pathophysiology of the disease. This insight has led to development and approval of small molecule inhibitors that target components of the BCR pathway. These advances have greatly improved the management of CLL, but the disease remains incurable. This may partly be explained by the inter-patient heterogeneity of the disease, also when it comes to treatment responses. Precision medicine is therefore required to optimize treatment and move towards a cure. Here, we discuss how the introduction of BCR signalling inhibitors has facilitated the development of functional in vitro assays to guide clinical treatment decisions on use of the same therapeutic agents in individual patients. The cellular responses to these agents can be analysed in high-throughput assays such as dynamic BH3 profiling, phospho flow experiments and drug sensitivity screens to identify predictive biomarkers. This progress exemplifies the positive synergy between basal and translational research needed to optimize patient care.
    MeSH term(s) Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors ; Agammaglobulinaemia Tyrosine Kinase/immunology ; Agammaglobulinaemia Tyrosine Kinase/metabolism ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; Class Ib Phosphatidylinositol 3-Kinase/immunology ; Class Ib Phosphatidylinositol 3-Kinase/metabolism ; Enzyme Inhibitors/therapeutic use ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Leukemia, Lymphocytic, Chronic, B-Cell/immunology ; Leukemia, Lymphocytic, Chronic, B-Cell/metabolism ; Molecular Targeted Therapy/methods ; Precision Medicine/methods ; Receptors, Antigen, B-Cell/antagonists & inhibitors ; Receptors, Antigen, B-Cell/immunology ; Receptors, Antigen, B-Cell/metabolism ; Signal Transduction/drug effects ; Signal Transduction/immunology
    Chemical Substances Enzyme Inhibitors ; Receptors, Antigen, B-Cell ; Class Ib Phosphatidylinositol 3-Kinase (EC 2.7.1.137) ; PIK3CG protein, human (EC 2.7.1.137) ; Agammaglobulinaemia Tyrosine Kinase (EC 2.7.10.2) ; BTK protein, human (EC 2.7.10.2)
    Language English
    Publishing date 2020-10-10
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 120476-2
    ISSN 1365-3083 ; 0300-9475
    ISSN (online) 1365-3083
    ISSN 0300-9475
    DOI 10.1111/sji.12931
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 806: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article: A tumor microenvironment model of chronic lymphocytic leukemia enables drug sensitivity testing to guide precision medicine.

    Hermansen, Johanne U / Yin, Yanping / Urban, Aleksandra / Myklebust, Camilla V / Karlsen, Linda / Melvold, Katrine / Tveita, Anders A / Taskén, Kjetil / Munthe, Ludvig A / Tjønnfjord, Geir E / Skånland, Sigrid S

    Cell death discovery

    2023  Volume 9, Issue 1, Page(s) 125

    Abstract: The microenvironment of chronic lymphocytic leukemia (CLL) cells in lymph nodes, spleen, and bone marrow provides survival, proliferation, and drug resistance signals. Therapies need to be effective in these compartments, and pre-clinical models of CLL ... ...

    Abstract The microenvironment of chronic lymphocytic leukemia (CLL) cells in lymph nodes, spleen, and bone marrow provides survival, proliferation, and drug resistance signals. Therapies need to be effective in these compartments, and pre-clinical models of CLL that are used to test drug sensitivity must mimic the tumor microenvironment to reflect clinical responses. Ex vivo models have been developed that capture individual or multiple aspects of the CLL microenvironment, but they are not necessarily compatible with high-throughput drug screens. Here, we report on a model that has reasonable associated costs, can be handled in a regularly equipped cell lab, and is compatible with ex vivo functional assays including drug sensitivity screens. The CLL cells are cultured with fibroblasts that express the ligands APRIL, BAFF and CD40L for 24 h. The transient co-culture was shown to support survival of primary CLL cells for at least 13 days, and mimic in vivo drug resistance signals. Ex vivo sensitivity and resistance to the Bcl-2 antagonist venetoclax correlated with in vivo responses. The assay was used to identify treatment vulnerabilities and guide precision medicine for a patient with relapsed CLL. Taken together, the presented CLL microenvironment model enables clinical implementation of functional precision medicine in CLL.
    Language English
    Publishing date 2023-04-13
    Publishing country United States
    Document type Journal Article
    ISSN 2058-7716
    ISSN 2058-7716
    DOI 10.1038/s41420-023-01426-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Functional Testing to Characterize and Stratify PI3K Inhibitor Responses in Chronic Lymphocytic Leukemia.

    Yin, Yanping / Athanasiadis, Paschalis / Karlsen, Linda / Urban, Aleksandra / Xu, Haifeng / Murali, Ishwarya / Fernandes, Stacey M / Arribas, Alberto J / Hilli, Abdul K / Taskén, Kjetil / Bertoni, Francesco / Mato, Anthony R / Normant, Emmanuel / Brown, Jennifer R / Tjønnfjord, Geir E / Aittokallio, Tero / Skånland, Sigrid S

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2022  Volume 28, Issue 20, Page(s) 4444–4455

    Abstract: Purpose: PI3K inhibitors (PI3Ki) are approved for relapsed chronic lymphocytic leukemia (CLL). Although patients may show an initial response to these therapies, development of treatment intolerance or resistance remain clinical challenges. To overcome ... ...

    Abstract Purpose: PI3K inhibitors (PI3Ki) are approved for relapsed chronic lymphocytic leukemia (CLL). Although patients may show an initial response to these therapies, development of treatment intolerance or resistance remain clinical challenges. To overcome these, prediction of individual treatment responses based on actionable biomarkers is needed. Here, we characterized the activity and cellular effects of 10 PI3Ki and investigated whether functional analyses can identify treatment vulnerabilities in PI3Ki-refractory/intolerant CLL and stratify responders to PI3Ki.
    Experimental design: Peripheral blood mononuclear cell samples (n = 51 in total) from treatment-naïve and PI3Ki-treated patients with CLL were studied. Cells were profiled against 10 PI3Ki and the Bcl-2 antagonist venetoclax. Cell signaling and immune phenotypes were analyzed by flow cytometry. Cell viability was monitored by detection of cleaved caspase-3 and the CellTiter-Glo assay.
    Results: pan-PI3Kis were most effective at inhibiting PI3K signaling and cell viability, and showed activity in CLL cells from both treatment-naïve and idelalisib-refractory/intolerant patients. CLL cells from idelalisib-refractory/intolerant patients showed overall reduced protein phosphorylation levels. The pan-PI3Ki copanlisib, but not the p110δ inhibitor idelalisib, inhibited PI3K signaling in CD4+ and CD8+ T cells in addition to CD19+ B cells, but did not significantly affect T-cell numbers. Combination treatment with a PI3Ki and venetoclax resulted in synergistic induction of apoptosis. Analysis of drug sensitivities to 73 drug combinations and profiling of 31 proteins stratified responders to idelalisib and umbralisib, respectively.
    Conclusions: Our findings suggest novel treatment vulnerabilities in idelalisib-refractory/intolerant CLL, and indicate that ex vivo functional profiling may stratify PI3Ki responders.
    MeSH term(s) Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Bridged Bicyclo Compounds, Heterocyclic ; Caspase 3 ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Leukocytes, Mononuclear/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Proto-Oncogene Proteins c-bcl-2/genetics ; Quinazolinones/pharmacology ; Quinazolinones/therapeutic use ; Sulfonamides
    Chemical Substances Antineoplastic Agents ; Bridged Bicyclo Compounds, Heterocyclic ; Phosphoinositide-3 Kinase Inhibitors ; Proto-Oncogene Proteins c-bcl-2 ; Quinazolinones ; Sulfonamides ; Caspase 3 (EC 3.4.22.-) ; venetoclax (N54AIC43PW)
    Language English
    Publishing date 2022-08-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-22-1221
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4223: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (2.OG)
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  4. Article ; Online: Mcl-1 and Bcl-xL levels predict responsiveness to dual MEK/Bcl-2 inhibition in B-cell malignancies.

    Melvold, Katrine / Giliberto, Mariaserena / Karlsen, Linda / Ayuda-Durán, Pilar / Hanes, Robert / Holien, Toril / Enserink, Jorrit / Brown, Jennifer R / Tjønnfjord, Geir E / Taskén, Kjetil / Skånland, Sigrid S

    Molecular oncology

    2021  Volume 16, Issue 5, Page(s) 1153–1170

    Abstract: Most patients with chronic lymphocytic leukemia (CLL) initially respond to targeted therapies, but eventually relapse and develop resistance. Novel treatment strategies are therefore needed to improve patient outcomes. Here, we performed direct drug ... ...

    Abstract Most patients with chronic lymphocytic leukemia (CLL) initially respond to targeted therapies, but eventually relapse and develop resistance. Novel treatment strategies are therefore needed to improve patient outcomes. Here, we performed direct drug testing on primary CLL cells and identified synergy between eight different mitogen-activated protein kinase kinase (MEK) inhibitors and the B-cell lymphoma 2 (Bcl-2) antagonist venetoclax. Drug sensitivity was independent of immunoglobulin heavy-chain gene variable region (IGVH) and tumor protein p53 (TP53) mutational status, and CLL cells from idelalisib-resistant patients remained sensitive to the treatment. This suggests that combined MEK/Bcl-2 inhibition may be an option for high-risk CLL. To test whether sensitivity could be detected in other B-cell malignancies, we performed drug testing on cell line models of CLL (n = 4), multiple myeloma (MM; n = 8), and mantle cell lymphoma (MCL; n = 7). Like CLL, MM cells were sensitive to the MEK inhibitor trametinib, and synergy was observed with venetoclax. In contrast, MCL cells were unresponsive to MEK inhibition. To investigate the underlying mechanisms of the disease-specific drug sensitivities, we performed flow cytometry-based high-throughput profiling of 31 signaling proteins and regulators of apoptosis in the 19 cell lines. We found that high expression of the antiapoptotic proteins myeloid cell leukemia-1 (Mcl-1) or B-cell lymphoma-extra large (Bcl-xL) predicted low sensitivity to trametinib + venetoclax. The low sensitivity could be overcome by combined treatment with an Mcl-1 or Bcl-xL inhibitor. Our findings suggest that MEK/Bcl-2 inhibition has therapeutic potential in leukemia and myeloma, and demonstrate that protein expression levels can serve as predictive biomarkers for treatment sensitivities.
    MeSH term(s) Adult ; Apoptosis ; Cell Line, Tumor ; Humans ; Leukemia ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Leukemia, Lymphocytic, Chronic, B-Cell/pathology ; Lymphoma, B-Cell/drug therapy ; Multiple Myeloma/drug therapy ; Proto-Oncogene Proteins c-bcl-2/metabolism
    Chemical Substances Proto-Oncogene Proteins c-bcl-2
    Language English
    Publishing date 2021-12-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2415106-3
    ISSN 1878-0261 ; 1574-7891
    ISSN (online) 1878-0261
    ISSN 1574-7891
    DOI 10.1002/1878-0261.13153
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 6637: Show issues Location:
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