ABSTRACT
BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: The data presented here provide the basis for further investigation of regimens including pimasertib in relapsed and refractory lymphomas.
Subject(s)
Class I Phosphatidylinositol 3-Kinases/genetics , Lymphoma, B-Cell/drug therapy , Niacinamide/analogs & derivatives , Protein-Tyrosine Kinases/genetics , Adenine/analogs & derivatives , Agammaglobulinaemia Tyrosine Kinase , Animals , Cell Line, Tumor , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Drug Synergism , Gene Expression Regulation, Neoplastic/drug effects , Humans , Lymphoma, B-Cell/genetics , Lymphoma, B-Cell/pathology , MAP Kinase Kinase Kinases/antagonists & inhibitors , MAP Kinase Kinase Kinases/genetics , Mice , Molecular Targeted Therapy , Niacinamide/administration & dosage , Piperidines , Protein-Tyrosine Kinases/antagonists & inhibitors , Purines/administration & dosage , Pyrazoles/administration & dosage , Pyrimidines/administration & dosage , Quinazolinones/administration & dosage , Signal Transduction/drug effects , Xenograft Model Antitumor AssaysSubject(s)
Chromosomes, Human, Pair 12/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Mutation/genetics , Receptor, Notch1/genetics , Trisomy/genetics , Disease Progression , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Prognosis , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
OBJECTIVE: To assess the efficacy and the mechanism of action of alpha-interferon (alpha-IFN) in the treatment of HIV-related thrombocytopenia. METHODS: Thirteen HIV-positive subjects [nine men and four women with severe thrombocytopenia (platelets, < or = 30 x 10(9)/l)] were treated with alpha-IFN 2b alone at a dose of 3 x 10(6) U three times a week for 5 weeks. Haematological parameters, platelet kinetic and bone-marrow myeloid progenitor cultures [megakaryocyte colony-forming units (CFU-MK); granulocyte macrophage CFU (CFU-GM) and erythroid burst-forming units (BFU-E)] were evaluated before and after treatment in responsive subjects. RESULTS: Seven out of 13 subjects showed a partial response (platelets, 50-149 x 10(9)/l) after alpha-IFN 2b therapy. Platelet survival as evaluated by 111In-oxine significantly increased, while platelet turnover showed a slight but not statistically significant increase after treatment. The growth of bone-marrow myeloid progenitor cells decreased after alpha-IFN 2b therapy, again without statistical significance. CONCLUSION: alpha-IFN 2b may increase the platelet count in HIV-positive subjects with severe symptomatic thrombocytopenia by prolonging platelet survival. The immunomodulatory and antiviral action of this drug may be responsible for prolonged platelet survival.