Kurzfassung

Flt3 (Fms-like tyrosine kinase 3) is a member of the class III receptor tyrosine kinase (RTK) family including FMS, platelet-derived growth factor receptor (PDGFR) and c-Kit. Flt3 is expressed by cells of the hematopoietic stem cell compartment and early myeloid progenitor cells. Stimulation of Flt3 by its ligand (Flt3 ligand , FL) synergizes with other hematopoietic growth factors and induces cellular proliferation of progenitor cells. Recent studies have demonstrated that mutations in the...Flt3 (Fms-like tyrosine kinase 3) is a member of the class III receptor tyrosine kinase (RTK) family including FMS, platelet-derived growth factor receptor (PDGFR) and c-Kit. Flt3 is expressed by cells of the hematopoietic stem cell compartment and early myeloid progenitor cells. Stimulation of Flt3 by its ligand (Flt3 ligand , FL) synergizes with other hematopoietic growth factors and induces cellular proliferation of progenitor cells. Recent studies have demonstrated that mutations in the FLT3 gene occur in about one third of adult patients with AML. In 20% - 27% of patients with AML, an internal tandem duplication (ITD) in the juxtamembrane region of FLT3 can be detected. Another 7% of patients have mutations within the activation loop of the second kinase domain, predominantly substitutions of aspartate at residue 835 (D835), while additional mutations at residues 836 and 840 have also been described. FLT3 mutations are detected at initial diagnosis of AML, but several patients have been reported to have gained new, secondary FLT3 mutations at relapse. Altogether, FLT3 is the single most commonly activated gene in AML. Mutations in FLT3 are associated with higher leukocyte and blast counts, an increased relapse rate and decreased overall survival. Expression of mutated Flt3 receptors results in constitutive tyrosine-phosphorylation of Flt3, subsequent activation of downstream signaling molecules such as STAT-5 and MAPK and factor independent growth of murine hematopoietic cell lines, resembling myeloproliferative disease in transplant models. Recently, clinical trials investigating the efficacy and toxicity of Flt-3 inhibitors have been started. Several small molecule inhibitors as PKC412, SU11248, CEP701, and MLN518 entered clinical trials. PKC412 is a N-benzoyl-staurosporine which is a highly potent inhibitor of both mutant and wild-type FLT3 tyrosine kinase, as revealed by in vitro and in vivo models. Preliminary results investigating PKC412 in patients with relapsed/refractory AML revealed that 11/15 patients (73%) with mutated FLT3 and 16/46 patients (35%) with WT FLT3 showed a > 50% blast response in peripheral blood (Estey E, Fischer T, Giles F, et al. Use of PKC412 in Patients with acute myeloid leukemia (AML)/High-Risk Myelodysplastic Syndromes (MDS) Characterized by Wild-Type (WT) or Mutated FLT3; A Randomized Trial of Two Doses. [ASH abstract]. Blood. 2003;102:919a).
Our hypothesis is that characterization of variations in oncogenic signaling in human AML is crucial to understand the spectrum of responses observed in clinical trials using Flt3 TK-inhibitors. In this project, we will investigate the relationship of molecular features with clinical responses and we will identify optimal approaches for the use of Flt3-inhibitors within combination therapies. We believe the findings anticipated will lead to a better understanding of malignant transformation of FLT3-mutated AML and to a rational development of effective therapeutic strategies.
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