semaxinib and Acute-Disease

Acute myelogenous leukemia (AML) is a difficult disease to treat. Novel treatment strategies, including molecular targeted therapy, are currently being explored. The c-kit receptor represents a potential therapeutic target for AML. The receptor is expressed on more than 10% of blasts in 64% of de novo AMLs and 95% of relapsed AMLs. C-kit mediates proliferation and anti-apoptotic effects in AML. This review will discuss the biology of c-kit in normal and malignant hematopoiesis, and the recent clinical trials targeting c-kit in AML.

Topics: Acute Disease; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Clinical Trials as Topic; Hematopoiesis; Humans; Imatinib Mesylate; Indoles; Leukemia, Myeloid; Mice; Oxindoles; Piperazines; Propionates; Protein Kinase Inhibitors; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-kit; Pyrimidines; Pyrroles; Stem Cell Factor

The acute myeloid leukemias (AML) are often fatal disorders with a range of clinical, morphologic, cytogenetic, and molecular features and a consequent need for a diverse array of therapies. This need for tailored therapy for subsets of patients with AML is exemplified in those with acute promyelocytic leukemia, the subject of a separate article in this issue (Tallman and Nabhan). Unfortunately, we tend to examine novel agents in patients with very advanced disease, in which prior therapies have inevitably altered the tumor. Of a myriad of possible exciting novel agents, a few, including PS-341, Genasense (Genta, Berkeley Heights, NJ), decitabine, 5-azacytidine, clofarabine, and troxacitabine, are briefly reviewed with an emphasis on their mechanisms of action from a perspective that suggests possible synergistic therapeutic interventions. With the growing appreciation of the pivotal role of angiogenesis in AML, angiogenesis modulators are a good example of a core class of drugs upon which future noncytotoxic combinations may be built. Those agents targeting vascular endothelial growth factor are also briefly reviewed.

Topics: Acute Disease; Adenine Nucleotides; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents; Arabinonucleosides; Azacitidine; Bevacizumab; Boronic Acids; Bortezomib; Clofarabine; Cytosine; Decitabine; Dioxolanes; Humans; Indoles; Leukemia, Myeloid; Phthalazines; Pyrazines; Pyridines; Pyrroles; Thionucleotides

Acute myeloid leukemia (AML) is associated with dysregulated hematopoietic cell proliferation and increased bone marrow angiogenesis, each regulated by signaling through receptor tyrosine kinases (RTKs). SU5416 is a small molecule inhibitor of VEGF receptors, c-kit and FLT3 and therefore provides a novel opportunity to target both angiogenesis and proliferation in AML. SU5416 was assessed in a phase II hematological malignancy trial in the US, where partial responses were observed in two of 33 patients. Since AML provides a unique platform to evaluate mechanism of action of small molecule inhibitors, investigation of the effect of SU5416 on FLT3 expression and phosphorylation in blood and bone marrow was an additional focus of this trial. Phosphorylated FLT3 was detected by immunoprecipitation/Western analysis in peripheral blood samples from 17 of 22 patients, and seven exhibited strong inhibition of phosphorylation immediately following a 1h SU5416 infusion, demonstrating that SU5416 can modulate RTK phosphorylation in humans. Although no clear correlation with clinical response was observed, analysis of patient plasma drug levels suggested that a threshold SU5416 concentration of 15 microM was associated with FLT3 inhibition. This observation was supported by data from an ex vivo model where AML cells were spiked into human blood, established to mimic the clinical setting and enable more rigorous analysis of effect of SU5416. In addition, FLT3 protein levels were downregulated in patient bone marrow samples, analyzed by an RIA assay. To identify putative predictors of response, patient plasma was analyzed for levels of secreted ligands of SU5416 targets; SCF and FLT3 ligand. Baseline levels of SCF in patients with stable or progressive disease were significantly higher than those in normal donors, whereas FLT3 ligand levels in patients who exhibited progressive disease were significantly lower than those in normal donors. The translational and clinical analyses described in this report provide some insights into the mechanism and duration of action of SU5416.

Topics: Acute Disease; Adult; Aged; Bone Marrow; Down-Regulation; Female; fms-Like Tyrosine Kinase 3; Humans; Indoles; Leukemia, Myeloid; Male; Membrane Proteins; Middle Aged; Mutation; Phosphorylation; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrroles; Receptor Protein-Tyrosine Kinases; Stem Cell Factor

Increased bone marrow angiogenesis and vascular endothelial growth factor (VEGF) levels are adverse prognostic features in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDSs). VEGF is a soluble circulating angiogenic molecule that stimulates signaling via receptor tyrosine kinases (RTKs), including VEGF receptor 2 (VEGFR-2). AML blasts may express VEGFR-2, c-kit, and FLT3. SU5416 is a small molecule RTK inhibitor (RTKI) of VEGFR-2, c-kit, and both wild-type and mutant FLT3. A multicenter phase 2 study of SU5416 was conducted in patients with refractory AML or MDS. For a median of 9 weeks (range, 1-55 weeks), 55 patients (33 AML: 10 [30%] primary refractory, 23 [70%] relapsed; 22 MDS: 15 [68%] relapsed) received 145 mg/m2 SU5416 twice weekly intravenously. Grade 3 or 4 drug-related toxicities included headaches (14%), infusion-related reactions (11%), dyspnea (14%), fatigue (7%), thrombotic episodes (7%), bone pain (5%), and gastrointestinal disturbance (4%). There were 11 patients (20%) who did not complete 4 weeks of therapy (10 progressive disease, 1 adverse event); 3 patients (5%) who achieved partial responses; and 1 (2%) who achieved hematologic improvement. Single agent SU5416 had biologic and modest clinical activity in refractory AML/MDS. Overall median survival was 12 weeks in AML patients (range, 4-41 weeks) and not reached in MDS patients. Most observed toxicities were attributable to drug formulation (polyoxyl 35 castor oil or hyperosmolarity of the SU5416 preparation). Studies of other RTKI and/or other antiangiogenic approaches, with correlative studies to examine biologic effects, may be warranted in patients with AML/MDS.

Topics: Acute Disease; Adult; Aged; Antineoplastic Agents; Apoptosis; Bone Marrow Cells; Bone Marrow Examination; Humans; Indoles; Leukemia, Myeloid; Middle Aged; Myelodysplastic Syndromes; Necrosis; Pharmacokinetics; Protein-Tyrosine Kinases; Pyrroles; Remission Induction; Salvage Therapy

The complex pathologies associated with severe pulmonary arterial hypertension (PAH) in humans have been a challenge to reproduce in mice due to the subtle phenotype displayed to PAH stimuli.. Here we aim to develop a novel murine model of PAH that recapitulates more of the pathologic processes, such as complex vascular remodeling and cardiac indices, that are not characteristic of alternative mouse models.. Inhibition of vascular endothelial growth factor receptor (VEGFR) with SU5416 combined with 3 weeks of chronic hypoxia was investigated. Hemodynamics, cardiac function, histological assessment of pulmonary vasculature, and molecular pathway analysis gauged the extent of PAH pathology development.. The combination of VEGFR inhibition with chronic hypoxia profoundly exacerbated all measures of PAH-like pathology when compared with hypoxia alone (> 45 mm Hg right ventricular pressure, > 0.35 right ventricular hypertrophy). The changes in pulmonary vascular remodeling in response to hypoxia were further enhanced on SU5416 treatment. Furthermore, hypoxia/SU5416 treatment steadily decreased cardiac output, indicating incipient heart failure. Molecular analysis showed a dysregulated transforming growth factor-β/bone morphogenetic protein/Smad axis in SU5416- and/or hypoxia-treated mice as well as augmented induction of IL-6 and Hif-1α levels. These changes were observed in accordance with up-regulation of Tph1 and Pdgfr gene transcripts as well as a rise in platelet-rich serotonin. Biomarker analysis in response to VEGFR inhibition and/or hypoxia revealed distinct signatures that correlate with cytokine profiles of patients with idiopathic PAH.. These data describe a novel murine model of PAH, which displays many of the hallmarks of the human disease, thus opening new avenues of investigation to better understand PAH pathophysiology.

Topics: Acute Disease; Animals; Blotting, Western; Cytokines; Disease Models, Animal; Echocardiography; Female; Fluorescent Antibody Technique; Gene Expression Profiling; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Indoles; Lung; Male; Mice; Mice, Inbred C57BL; Pyrroles; Receptors, Vascular Endothelial Growth Factor

FLT3 receptor tyrosine kinase is aberrantly active in many cases of acute myeloid leukemia (AML). Recently, bis(1H-indol-2-yl)methanones were found to inhibit FLT3 and PDGFR kinases. To optimize FLT3 activity and selectivity, 35 novel derivatives were synthesized and tested for inhibition of FLT3 and PDGFR autophosphorylation. The most potent FLT3 inhibitors 98 and 102 show IC50 values of 0.06 and 0.04 microM, respectively, and 1 order of magnitude lower PDGFR inhibiting activity. The derivatives 76 and 82 are 20- to 40-fold PDGFR selective. Docking at the recent FLT3 structure suggests a bidentate binding mode with the backbone of Cys-694. Activity and selectivity can be related to interactions of one indole moiety with a hydrophobic pocket including Phe-691, the only different binding site residue (PDGFR Thr-681). Compound 102 inhibited the proliferation of 32D cells expressing wildtype FLT3 or FLT3-ITD similarly as FLT3 autophosphorylation, and induced apoptosis in primary AML patient blasts.

Topics: Acute Disease; Animals; Antineoplastic Agents; Apoptosis; Binding Sites; Cell Line; Cell Line, Tumor; fms-Like Tyrosine Kinase 3; Humans; In Vitro Techniques; Indoles; Leukemia, Myeloid; Ligands; Mice; Models, Molecular; Phosphorylation; Pyrroles; Receptors, Platelet-Derived Growth Factor; Structure-Activity Relationship

The small molecule receptor tyrosine kinase (RTK) inhibitor SU5416 targets the vascular endothelial growth factor receptor 2 and the stem cell factor receptor c-kit. Herein is described the successful treatment of a 65-year-old woman with SU5416, in second relapse of acute myeloid leukemia (AML) and refractory toward standard chemotherapy regimens. After 12 weeks of treatment with SU5416, the blast cell counts (blood and bone marrow) decreased to undetectable levels and the peripheral blood cell counts normalized with the exception of the platelet count (50-80 x 10(9)/L [50-80 x 10(3)/microL]). The duration of the remission is longer than 4 months during maintenance therapy with SU5416. Microvessel density in the patient's bone marrow dropped from 33.4 to 12.3 microvessels/x500-field 8 weeks after SU5416 administration and remains in the normal range. This is the first report of a stable remission achieved after administration of the RTK inhibitor SU5416 in a patient with AML relapse.

Topics: Acute Disease; Angiogenesis Inhibitors; Antineoplastic Agents; Bone Marrow Cells; Endothelium, Vascular; Female; Humans; Immunohistochemistry; Indoles; Leukemia, Myeloid; Middle Aged; Protein-Tyrosine Kinases; Pyrroles; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor; Remission Induction