semaxinib and midostaurin

The pathological role of bone marrow angiogenesis in human leukemias has been clearly established. Bone marrow neoangiogenesis is mediated by several growth factors, such as VEGF-A, VEGF-C, angiopoietin-1 and -2, FGF, HGF, TGF-β and others secreted by leukemic cells. The prognostic relevance of microvessel density, and expression of VEGF-A and -C has been demonstrated especially in acute myeloid leukemia. In the last years, several classes of angiogenesis inhibitors have been developed blocking several angiogenic pathways. These include drugs that inhibit the VEGF (with or without blockade of FLT3) and the mTor signalling cascade. Besides, thalidomide and lenalidomide although possessing a pleiotrophic mode of action including antiangiogenic properities have been evaluated in the treatment of human leukemias. In the current review we analyze the results of clinical trials employing these antiangiogenic drugs. Since the clinical efficacy of these compounds used as monotherapy is often limited, confined to certain subgroups of patients and frequently short lived, several trials combining standard chemotherapy with these agents have been initiated in order to demonstrate an additional benefit to standard therapy. Furthermore the introduction of new antiangiogenic drugs such as inhibitors of the angiopoietin and HGF/cMET pathway is on the horizon. Utilizing cocktails of inhibitors of several angiogenic pathways may represent a new possibility to augment the efficacy of antiangiogenic therapy in the future.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Benzenesulfonates; Bevacizumab; Clinical Trials as Topic; Humans; Indoles; Lenalidomide; Leukemia; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Quinazolines; Sorafenib; Staurosporine; Sunitinib; Thalidomide; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Acute myeloid leukaemia (AML) is characterised by the infiltration of the bone marrow with highly proliferative leukaemic cells that stop to differentiate at different stages of myeloid development and carry survival advantages. Conventionally, AML is treated with aggressive cytotoxic therapy, in eligible patients followed by allogeneic bone marrow transplantation. However, despite this aggressive treatment, many patients relapse and eventually die from the disease. Activating mutations in the coding sequence of the receptor tyrosine kinase Flt3 are found in leukaemic blasts from approximately 30% of AML patients. The mutations have been described to severely alter the signalling properties of this receptor and to have transforming activity in cell-line models and in primary mouse bone marrow. The prognosis of patients harbouring the most common Flt3 mutations tends to be worse than that of comparable patients without the mutations. Thus, Flt3 seems a promising target for therapeutic intervention. Several small molecules that inhibit Flt3 kinase activity are being evaluated for the treatment of AML in clinical trials. This review article discusses the signal transduction and biological function of Flt3 and its mutations in normal and malignant haematopoiesis and recent progress in drug development aiming at the inhibition of Flt3 kinases.

Topics: Animals; Antineoplastic Agents; Carbazoles; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Therapy, Combination; fms-Like Tyrosine Kinase 3; Furans; Humans; Indoles; Leukemia, Myeloid, Acute; Mutation; Protein Kinase Inhibitors; Pyrroles; Signal Transduction; Staurosporine