Jebsen Centre for B Cell Malignancies, Institute of Clinical Medicine, University of Oslo, Oslo, Norway, 3Department of Haematology, Oslo University Hospital, Oslo, Norway, 4Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway, 5Oslo Centre for Biostatistics and Epidemiology (OCBE), Faculty of Medicine, University of Oslo, Oslo, Norway, 6Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA, 7Department of Medicine, Diakonhjemmet Hospital, Oslo, Norway, 8Institute of Oncology Research, Faculty of Biomedical Sciences, USI, 6500 Bellinzona, Switzerland. Skånland1,2ġDepartment of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway, 2K. Tjønnfjord2,3, Tero Aittokallio4,5,13, Sigrid S. Hilli7, Kjetil Taskén1,2, Francesco Bertoni8,9, Anthony R. ![]() Yanping Yin1,2,3, Paschalis Athanasiadis4,5, Linda Karlsen1,2, Aleksandra Urban1,2, Ishwarya Murali6, Stacey M. All rights reserved.įunctional screening of PI3K inhibitors stratifies responders to idelalisib and indicates drug class activity in idelalisib-refractory CLL Taken together, targeting the α- and δ- p110 isoforms with copanlisib may be a useful strategy for the treatment of CLL and warrants further clinical investigation. Survival inhibition by copanlisib and idelalisib was enhanced by the monoclonal CD20 antibodies rituximab and obinutuzumab (GA101), while antibody-dependent cellular cytotoxicity mediated by alemtuzumab and peripheral blood mononuclear cells was not substantially impaired by both PI3K inhibitors for the CLL-derived JVM-3 cell line as target cells. Similarly copanlisib and duvelisib reduced the survival of CLL cells in co-cultures with the bone marrow stroma cell line HS-5 more strongly than idelalisib. In addition copanlisib and duvelisib impaired the migration of CLL cells towards CXCL12 to a greater extent than equimolar idelalisib. Copanlisib selectively reduced the survival of CLL cells compared to T cells and to B cells from healthy donors. ![]() At concentrations reflecting the biological availability of the different inhibitors, high levels of apoptotic response among CLL samples were attained more consistently with copanlisib than with idelalisib. The concentrations leading to half-maximal reduction of the survival of CLL cells were more than ten-fold lower for copanlisib than for idelalisib and duvelisib. 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. 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. Pharmacological inhibition of phosphatiylinositide-3-kinase (PI3K)-mediated signaling holds great promise for treating chronic lymphocytic leukemia (CLL).
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