midostaurin and Myeloproliferative-Disorders
midostaurin has been researched along with Myeloproliferative-Disorders* in 8 studies
Reviews
2 review(s) available for midostaurin and Myeloproliferative-Disorders
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Emerging translational science discoveries, clonal approaches, and treatment trends in chronic myeloproliferative neoplasms.
The 60th American Society of Hematology (ASH) held in San Diego in December 2018 was followed by the 13th Post-ASH chronic myeloproliferative neoplasms (MPNs) workshop on December 4 and 5, 2018. This closed annual workshop, first introduced in 2006 by Goldman and Mughal, was organized in collaboration with Alpine Oncology Foundation and allowed experts in preclinical and clinical research in the chronic MPNs to discuss the current scenario, including relevant presentations at ASH, and address pivotal open questions that impact translational research and clinical management. This review is based on the presentations and deliberations at this workshop, and rather than provide a resume of the proceedings, we have selected some of the important translational science and treatment issues that require clarity. We discuss the experimental and observational evidence to support the intimate interaction between aging, inflammation, and clonal evolution of MPNs, the clinical impact of the unfolding mutational landscape on the emerging targets and treatment of MPNs, new methods to detect clonal heterogeneity, the challenges in managing childhood and adolescent MPN, and reflect on the treatment of systemic mastocytosis (SM) following the licensing of midostaurin. Topics: Aging; Animals; Congresses as Topic; DNA Mutational Analysis; Humans; Inflammation; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mastocytosis; Medical Oncology; Mice; Mutation; Myeloproliferative Disorders; Prognosis; Societies, Medical; Staurosporine; Translational Research, Biomedical; United States | 2019 |
Recent advances in the genomics and therapy of BCR/ABL1-positive and -negative chronic myeloproliferative neoplasms.
This review is based on the presentations and deliberations at the 7th John Goldman Chronic Myeloid Leukemia (CML) and Myeloproliferative Neoplasms (MPN) Colloquium which took place in Estoril, Portugal on the 15th October 2017, and the 11th post-ASH International Workshop on CML and MPN which took place on the 6th-7th December 2016, immediately after the 58th American Society of Hematology Annual Meeting. Rather than present a resume of the proceedings, we have elected to address some of the topical translational research and clinically relevant topics in greater detail. We address recent updates in the genetics and epigenetics of MPN, the mechanisms of transformation by mutant calreticulin, advances in the biology and therapy of systemic mastocytosis, clinical updates on JAK2 inhibitors and other therapeutic approaches for patients with MPNs, cardiovascular toxicity related to tyrosine kinase inhibitors and the concept of treatment-free remission for patients with CML. Topics: Antineoplastic Agents; Calreticulin; Cardiovascular Diseases; Cell Transformation, Neoplastic; Chronic Disease; Congresses as Topic; Epigenesis, Genetic; Fusion Proteins, bcr-abl; Humans; Janus Kinase 2; Mastocytosis, Systemic; Mutation; Myeloproliferative Disorders; Protein Kinase Inhibitors; Remission Induction; Staurosporine; Translational Research, Biomedical | 2018 |
Other Studies
6 other study(ies) available for midostaurin and Myeloproliferative-Disorders
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Screening of drugs to treat 8p11 myeloproliferative syndrome using patient-derived induced pluripotent stem cells with fusion gene CEP110-FGFR1.
Induced pluripotent stem (iPS) cells provide powerful tools for studying disease mechanisms and developing therapies for diseases. The 8p11 myeloproliferative syndrome (EMS) is an aggressive chronic myeloproliferative disorder (MPD) that is caused by constitutive activation of fibroblast growth factor receptor 1. EMS is rare and, consequently, effective treatment for this disease has not been established. Here, iPS cells were generated from an EMS patient (EMS-iPS cells) to assist the development of effective therapies for EMS. When iPS cells were co-cultured with murine embryonic stromal cells, EMS-iPS cells produced more hematopoietic progenitor and hematopoietic cells, and CD34+ cells derived from EMS-iPS cells exhibited 3.2-7.2-fold more macrophage and erythroid colony forming units (CFUs) than those derived from control iPS cells. These data indicate that EMS-iPS cells have an increased hematopoietic differentiation capacity, which is characteristic of MPDs. To determine whether a tyrosine kinase inhibitor (TKI) could suppress the increased number of CFUs formed by EMS-iPS-induced CD34+ cells, cells were treated with one of four TKIs (CHIR258, PKC 412, ponatinib, and imatinib). CHIR258, PKC 412, and ponatinib reduced the number of CFUs formed by EMS-iPS-induced CD34+ cells in a dose-dependent manner, whereas imatinib did not. Similar effects were observed on primary peripheral blood cells (more than 90% of which were blasts) isolated from the patient. This study provides evidence that the EMS-iPS cell line is a useful tool for the screening of drugs to treat EMS and to investigate the mechanism underlying this disease. Topics: Adolescent; Benzimidazoles; Cells, Cultured; Drug Evaluation, Preclinical; Hematopoiesis; Humans; Imatinib Mesylate; Imidazoles; Induced Pluripotent Stem Cells; Male; Myeloproliferative Disorders; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyridazines; Quinolones; Receptor, Fibroblast Growth Factor, Type 1; Staurosporine; Translocation, Genetic | 2015 |
The hypereosinophilic syndrome: idiopathic or not, that is the question.
Topics: Antineoplastic Agents; Benzamides; Chromosome Deletion; Chromosomes, Human, Pair 4; Chronic Disease; Clone Cells; Diagnosis, Differential; Drug Resistance, Neoplasm; Humans; Hypereosinophilic Syndrome; Imatinib Mesylate; In Situ Hybridization, Fluorescence; Lymphoproliferative Disorders; mRNA Cleavage and Polyadenylation Factors; Myeloproliferative Disorders; Oncogene Proteins, Fusion; Piperazines; Point Mutation; Protein Kinase Inhibitors; Protein Structure, Tertiary; Pyrimidines; Receptor, Platelet-Derived Growth Factor alpha; Staurosporine; T-Lymphocyte Subsets | 2005 |
FGFR3 as a therapeutic target of the small molecule inhibitor PKC412 in hematopoietic malignancies.
Reccurent chromosomal translocation t(4;14) (p16.3;q32.3) occurs in patients with multiple myeloma (MM) and is associated with ectopic overexpression of fibroblast growth factor receptor 3 (FGFR3) that sometimes may contain the activation mutations such as K650E thanatophoric dysplasia type II (TDII). Although there have been significant advances in therapy for MM including the use of proteasome inhibitors, t(4;14) MM has a particularly poor prognosis and most patients still die from complications related to their disease or therapy. One potential therapeutic strategy is to inhibit FGFR3 in those myeloma patients that overexpress the receptor tyrosine kinase due to chromosomal translocation. Here we evaluated PKC412, a small molecule tyrosine kinase inhibitor, for treatment of FGFR3-induced hematopoietic malignancies. PKC412 inhibited kinase activation and proliferation of hematopoietic Ba/F3 cells transformed by FGFR3 TDII or a TEL-FGFR3 fusion. Similar results were obtained in PKC412 inhibition of several different t(4;14)-positive human MM cell lines. Furthermore, treatment with PKC412 resulted in a statistically significant prolongation of survival in murine bone marrow transplant models of FGFR3 TDII-induced pre-B cell lymphoma, or a peripheral T-cell lymphoma associated TEL-FGFR3 fusion-induced myeloproliferative disease. These data indicate that PKC412 may be a useful molecularly targeted therapy for MM associated with overexpression of FGFR3, and perhaps other diseases associated with dysregulation of FGFR3 or related mutants. Topics: Animals; Bone Marrow Transplantation; Cell Line, Tumor; Disease Models, Animal; Growth Inhibitors; Hematologic Neoplasms; Lymphoma, B-Cell; Mice; Multiple Myeloma; Myeloproliferative Disorders; Protein-Tyrosine Kinases; Receptor, Fibroblast Growth Factor, Type 3; Recombinant Fusion Proteins; Staurosporine; Thanatophoric Dysplasia; Transfection | 2005 |
FLT3 internal tandem duplication mutations induce myeloproliferative or lymphoid disease in a transgenic mouse model.
Activating FMS-like tyrosine kinase 3 (FLT3) mutations have been identified in approximately 30% of patients with acute myelogenous leukemia (AML), and recently in a smaller subset of patients with acute lymphoblastic leukemia (ALL). To explore the in vivo consequences of an activating FLT3 internal tandem duplication mutation (FLT3-ITD), we created a transgenic mouse model in which FLT3-ITD was expressed under the control of the vav hematopoietic promoter. Five independent lines of vav-FLT3-ITD transgenic mice developed a myeloproliferative disease with high penetrance and a disease latency of 6-12 months. The phenotype was characterized by splenomegaly, megakaryocytic hyperplasia, and marked thrombocythemia, but without leukocytosis, polycythemia, or marrow fibrosis, displaying features reminiscent of the human disease essential thrombocythemia (ET). Clonal immature B- or T-lymphoid disease was observed in two additional founder mice, respectively, that could be secondarily transplanted to recipient mice that rapidly developed lymphoid disease. Treatment of these mice with the FLT3 tyrosine kinase inhibitor, PKC412, resulted in suppression of disease and a statistically significant prolongation of survival. These results demonstrate that FLT3-ITD is capable of inducing myeloproliferative as well as lymphoid disease, and indicate that small-molecule tyrosine kinase inhibitors may be an effective treatment for lymphoid malignancies in humans that are associated with activating mutations in FLT3. Topics: Animals; Disease Models, Animal; fms-Like Tyrosine Kinase 3; Gene Duplication; Humans; Leukemia; Lymphoma; Mice; Mice, Transgenic; Mutation; Myeloproliferative Disorders; Phenotype; Promoter Regions, Genetic; Protein Kinase C; Staurosporine | 2005 |
PKC412 inhibits the zinc finger 198-fibroblast growth factor receptor 1 fusion tyrosine kinase and is active in treatment of stem cell myeloproliferative disorder.
Human stem cell leukemia-lymphoma syndrome usually presents itself as a myeloproliferative disorder (MPD) that evolves to acute myeloid leukemia and/or lymphoma. The syndrome associated with t(8;13)(p11;q12) results in expression of the ZNF198-fibroblast growth factor receptor (FGFR) 1 fusion tyrosine kinase. Current empirically derived cytotoxic chemotherapy is inadequate for treatment of this disease. We hypothesized that small-molecule inhibitors of the ZNF198-FGFR1 fusion would have therapeutic efficacy. We characterized the transforming activity of ZNF198-FGFR1 in hematopoietic cells in vitro and in vivo. Expression of ZNF198-FGFR1 in primary murine hematopoietic cells caused a myeloproliferative syndrome in mice that recapitulated the human MPD phenotype. Transformation in these assays, and activation of the downstream effector molecules PLC-gamma, STAT5, and phosphatidylinositol 3-kinase/AKT, required the proline-rich domains, but not the ZNF domains, of ZNF198. A small-molecule tyrosine kinase inhibitor, PKC412 (N-benzoyl-staurosporine) effectively inhibited ZNF198-FGFR1 tyrosine kinase activity and activation of downstream effector pathways, and inhibited proliferation of ZNF198-FGFR1 transformed Ba/F3 cells. Furthermore, treatment with PKC412 resulted in statistically significant prolongation of survival in the murine model of ZNF198-FGFR1-induced MPD. Based in part on these data, PKC412 was administered to a patient with t(8;13)(p11;q12) and was efficacious in treatment of progressive myeloproliferative disorder with organomegaly. Therefore, PKC412 may be a useful therapy for treatment of human stem cell leukemia-lymphoma syndrome. Topics: Animals; Cell Line; Chromosomes, Human, Pair 13; Chromosomes, Human, Pair 8; Disease Models, Animal; Female; Genetic Variation; Humans; In Vitro Techniques; Mice; Mice, Inbred BALB C; Middle Aged; Myeloproliferative Disorders; Receptor Protein-Tyrosine Kinases; Receptor, Fibroblast Growth Factor, Type 1; Receptors, Fibroblast Growth Factor; Staurosporine; Transformation, Genetic; Translocation, Genetic; Zinc Fingers | 2004 |
PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRα-induced myeloproliferative disease.
FIP1L1-PDGFRalpha causes hypereosinophilic syndrome (HES) and is inhibited by the tyrosine kinase inhibitor imatinib (Gleevec). Imatinib is a potent inhibitor of ABL, ARG, PDGFRalpha, PDGFRbeta, and KIT and induces durable hematologic responses in HES patients. However, we observed relapse with resistance to imatinib as consequence of a T674I mutation in FIP1L1-PDGFRalpha, analogous to the imatinib-resistant T315I mutation in BCR-ABL. We developed a murine bone marrow transplant model of FIP1L1-PDGFRalpha-induced myeloproliferative disease to evaluate the efficacy of PKC412, an alternative inhibitor of PDGFRalpha, for the treatment of HES. PKC412 is effective for treatment of FIP1L1-PDGFRalpha-induced disease and of imatinib-induced resistance due to the T674I mutation. Our data establish PKC412 as molecularly targeted therapy for HES and other diseases expressing activated PDGFRalpha and demonstrate the potential of alternative kinase inhibitors to overcome resistance in target tyrosine kinases. Topics: Animals; Antineoplastic Agents; Benzamides; Blotting, Western; Bone Marrow; Bone Marrow Transplantation; Cell Line; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance; Fusion Proteins, bcr-abl; Genetic Vectors; Humans; Imatinib Mesylate; Immunophenotyping; Mice; Models, Genetic; mRNA Cleavage and Polyadenylation Factors; Mutation; Myeloproliferative Disorders; Piperazines; Precipitin Tests; Pyrimidines; Receptor, Platelet-Derived Growth Factor alpha; Recurrence; Retroviridae; Spleen; Staurosporine; Time Factors | 2003 |