leupeptins and Lymphoma--Large-B-Cell--Diffuse

The proteasome, which plays a pivotal role in the control of many cell cycle-regulatory processes, has become the focus of new approaches to the treatment of cancer, including B-cell malignancies, and the first proteasome inhibitor, bortezomib (VELCADE; formerly PS-341), has entered clinical trials. The proteasome controls the stability of numerous proteins that regulate progression through the cell cycle and apoptosis, such as cyclins, cyclin-dependent kinases, tumor suppressors, and the nuclear factor-kB. By altering the stability or activity of these proteins, proteasome inhibitors sensitize malignant cells to apoptosis. Bortezomib is a dipeptidyl boronic acid proteasome inhibitor that effectively and specifically inhibits proteasome activity. In preclinical studies, bortezomib and other proteasome inhibitors have shown activity against a variety of B-cell malignancies, including multiple myeloma, diffuse large B-cell lymphoma, mantle cell lymphoma, and Hodgkin's lymphoma. These agents can induce apoptosis and sensitize tumor cells to radiation or chemotherapy. Based on these findings, phase I clinical trials were conducted with bortezomib in various solid and hematologic malignancies. In these studies, bortezomib was generally well tolerated with manageable toxicities. Phase II trials have been initiated for relapsed and refractory multiple myeloma, refractory chronic lymphocytic leukemia, and non-Hodgkin's lymphoma. Preliminary data from the multiple myeloma phase II study indicate that a significant number of patients responded to therapy or exhibited stable disease and that the drug had manageable toxicities. These findings, along with extensive preclinical data, suggest that bortezomib and other proteasome inhibitors may have far-reaching potential in the treatment of various cancers, including B-cell malignancies.

Topics: Acetylcysteine; Animals; Boronic Acids; Bortezomib; Cell Cycle Proteins; Clinical Trials as Topic; Drug Screening Assays, Antitumor; Enzymes; Gene Expression Regulation; Hodgkin Disease; Humans; Leukemia, B-Cell; Leupeptins; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Mice; Multiple Myeloma; Neoplasm Proteins; NF-kappa B; Oncogene Proteins; Peptide Hydrolases; Protease Inhibitors; Proteasome Endopeptidase Complex; Pyrazines; Substrate Specificity; Transcription Factors; Treatment Outcome

BH3 mimetics like venetoclax target prosurvival Bcl-2 family proteins and are important therapeutics in the treatment of hematological malignancies. We demonstrate that endogenous Bfl-1 expression can render preclinical lymphoma tumor models insensitive to Mcl-1 and Bcl-2 inhibitors. However, suppression of Bfl-1 alone was insufficient to fully induce apoptosis in Bfl-1-expressing lymphomas, highlighting the need for targeting additional prosurvival proteins in this context. Importantly, we demonstrated that cyclin-dependent kinase 9 (CDK9) inhibitors rapidly downregulate both Bfl-1 and Mcl-1, inducing apoptosis in BH3-mimetic-resistant lymphoma cell lines in vitro and driving in vivo tumor regressions in diffuse large B-cell lymphoma patient-derived xenograft models expressing Bfl-1. These data underscore the need to clinically develop CDK9 inhibitors, like AZD4573, for the treatment of lymphomas using Bfl-1 as a selection biomarker.

Topics: Animals; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cyclin-Dependent Kinase 9; Cycloheximide; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Leupeptins; Lymphoma, Large B-Cell, Diffuse; Macrocyclic Compounds; Mice; Mice, Inbred NOD; Mice, SCID; Minor Histocompatibility Antigens; Molecular Targeted Therapy; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins; Peptide Fragments; Piperazines; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Pyridines; Sulfonamides; Xenograft Model Antitumor Assays

The endoplasmic reticulum kinase inositol-requiring enzyme 1 (IRE1) and its downstream target X-box-binding protein 1 (XBP1) drive B-cell differentiation toward plasma cells and have been shown to contribute to multiple myeloma development; yet, little is known of the role of this pathway in diffuse large B-cell lymphoma (DLBCL). Here, we show that in the germinal center B-cell-like (GCB) DLBCL subtype, IRE1 expression is reduced to a level that prevents XBP1 activation. Gene expression profiles indicated that, in GCB DLBCL cancer samples, expression of

Topics: Animals; B-Lymphocytes; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Endoribonucleases; Enhancer of Zeste Homolog 2 Protein; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Germinal Center; Histones; Humans; Indazoles; Leupeptins; Lymphoma, Large B-Cell, Diffuse; Mice; Mice, 129 Strain; Plasma Cells; Promoter Regions, Genetic; Protein Serine-Threonine Kinases; Pyridones; RNA, Messenger; Signal Transduction; X-Box Binding Protein 1; Xenograft Model Antitumor Assays