A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia

Fiedler, Walter; Mesters, Rolf M.; Tinnefeld, Heike; Loges, Sonja; Staib, Peter; Dührsen, Ulrich; Flaßhove, Michael; Ottmann, Oliver G.; Jung, Wolfram; Cavalli, Franco; Kuse, R.; Thomalla, Joerg; Serve, Hubert; O’Farrell, Anne; Jacobs, Mark; Brega, Nicoletta; Scigalla, P.; Hossfeld, Dieter K.; Berdel, Wolfgang E.

doi:10.1182/blood-2002-10-2998

Cited by 241 publications

(153 citation statements)

References 15 publications

(8 reference statements)

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Section: Resultsmentioning

confidence: 62%

“…As an additional control, treatment with up to 1 M imatinib mesylate had no effect on Ba/F3-N841I cells in the absence of IL-3 (data not shown) and had no effect on receptor phosphorylation. Taken together, these results suggest that the N841I mutation, like other FLT3 mutations, 11,16,22,23 results in constitutive kinase activation and factor-independent proliferation of Ba/F3 cells.Immunoblot analysis of the FLT3-N841I cells revealed constitutive phosphorylation of STAT5 in the absence of IL-3 and ERK phosphorylation on tyrosine 204. These phosphorylation events were reduced by treatment with PKC412 at concentrations as low as 0.01 M (Figure 3B), and this inhibition was reversed by treatment with IL-3.…”

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confidence: 62%

“…10,14 In phase-1 and -2 clinical trials, FLT3 inhibitors have reduced FLT3 phosphorylation [15][16][17] and leukemia blast counts and have induced clinical responses in patients with advanced therapy-refractive AML. 17,18 In this report, we identified novel point mutations in 3 patients with AML that result in a substitution of isoleucine for asparagine 841 in 2 patients and of tyrosine for asparagine 841 in another patient.…”

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confidence: 99%

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Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML

Jiang

Páez

Lee

et al. 2004

Blood

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The FLT3 receptor is activated by juxtamembrane insertion mutations and by activation loop point mutations in patients with acute myeloid leukemia (AML). In a systematic tyrosine kinase gene exon resequencing study, 21 of 24 FLT3 exons were sequenced in samples from 53 patients with AML, 9 patients with acute lymphoblastic leukemia (ALL), and 3 patients with myelodysplasia samples. Three patients had novel point mutations at residue N841 that resulted in a change to isoleucine in 2 samples and to tyrosine in 1 sample. Introduction of FLT3-N841I cDNA into Ba/F3 cells led to interleukin-3 (IL-3)-independent proliferation, receptor phosphorylation, and constitutive activation of signal transducer and activator of transcription 5 (STAT5) and extracellular regulatory kinase (ERK), suggesting that the N841I mutation confers constitutive activity to the receptor. An FLT3 inhibitor (PKC412) inhibited the growth of Ba/F3-FLT3N841I cells (IC 50 10 nM), but not of wild-type Ba/F3 cells cultured with IL-3. PKC412 also reduced tyrosine phosphorylation of the mutant receptor and inhibited STAT5 phosphorylation. Examination of the FLT3 autoinhibited structure showed that N841 is the key residue in a hydrogen-bonding network that likely stabilizes the activation loop. These results suggest that mutations at N841 represent a significant new activating mutation in patients with AML and that patients with such mutations may respond to smallmolecule FLT3 inhibitors such as PKC412. IntroductionFLT3, a class 3 receptor tyrosine kinase, is targeted and activated by somatic mutation in acute myeloid leukemia (AML). Internal tandem duplication (ITD) mutations of the FLT3 juxtamembrane (JM) occur in approximately 24% of patients with AML and in 15% of patients with secondary AML 1,2 and are associated with shortened disease-free survival. 3 Mutations in the activation loop (AL), typically D835Y, occur in approximately 7% of patients with AML and 3% of patients with myelodysplastic syndromes (MDS) 4,5 and in patients with T-cell ALL (T-ALL). 6 An increased frequency of FLT3 mutations has also been associated with mutations involving the mixed-lineage leukemia (MLL) gene. 7 ITD and AL mutations result in constitutive FLT3 kinase activity. When FLT3 receptors harboring such mutations are introduced into mammalian cells, downstream signaling pathways are activated that lead to factor-independent growth in vitro and to leukemogenesis in vivo. 8,9 For example, the production of FLT3-ITD mutant proteins in primary murine bone marrow cells results in a lethal myeloproliferative phenotype. 10 Thus, FLT3 is a leukemia oncogene, and activating FLT3 mutations likely contribute significantly to the development of leukemia in humans.Several small-molecule inhibitors block the kinase activity of FLT3 with high potency 10-13 (eg, PKC412, MLN518, SU11248) and can prolong the lifespans of mice harboring leukemias expressing mutant FLT3 receptors. 10,14 In phase-1 and -2 clinical trials, FLT3 inhibitors have reduced FLT3 phosphorylation 15-17 and leukemia...

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Section: Resultsmentioning

confidence: 62%

mentioning

confidence: 62%

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confidence: 99%

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Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML

Jiang

Páez

Lee

et al. 2004

Blood

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“…However, these observations were not confirmed by a recently performed phase II trial. 44 Although initial results from clinical trials in acute leukemia 45 showed a favorable outcome for patients taking SU5416, results from phase II studies for melanoma, 46 multiple myeloma, 47 and renal cancer 48 diminish original enthusiasm. No clinical trial has been performed so far regarding the efficacy of VEGFR-2 inhibitors as adjuvant chemotherapy in patients with head and neck cancer.…”

Section: Discussionmentioning

confidence: 99%

Potential autocrine function of vascular endothelial growth factor in head and neck cancer via vascular endothelial growth factor receptor-2

et al. 2005

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Vascular endothelial growth factor is a peptide with well-defined actions on the vasculature and fundamental role in tumor angiogenesis. Its action in vascular endothelium is exerted in a paracrine manner. The immunohistochemical expression of this protein by cancer cells in head and neck squamous cell carcinoma was correlated with increased tumor aggressiveness and poor survival in previous studies. In the past years, an increasing amount of studies demonstrated potential autocrine action of vascular endothelial growth factor in various neoplasms. However, the existence and the impact of such autocrine action in head and neck cancer have not been demonstrated yet. In this retrospective study, we evaluated the expression of vascular endothelial growth factor and its receptors in neoplastic cells, in a cohort of patients with head and neck squamous cell carcinoma, and compared this expression with tumor aggressiveness, clinicopathologic parameters and outcome. High expression of vascular endothelial growth factor was strongly correlated with high expression of vascular endothelial growth factor receptor-2 (but not vascular endothelial growth factor receptor-1) on the cancer cells (Po0.001). The co-overexpression of both the protein and vascular endothelial growth factor receptor-2 was associated with higher tumor proliferation rate (Po0.001). The above cooverexpression also correlated with worse survival (log rank Po0.05) in patients with oral-larynx squamous cell carcinoma. Our results suggest that an autocrine vascular endothelial growth factor loop, mediated via vascular endothelial growth factor receptor-2, probably exists in head and neck squamous cell carcinoma. These observations support the hypothesis that the use of vascular endothelial growth factor receptor-2 inhibitors as adjuvant antiangiogenic therapy might have beneficial effects for these patients, by disrupting both paracrine (endothelial-dependent) and autocrine actions of vascular endothelial growth factor.

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“…Thus, targeting FLT3-ITD may improve prognosis by enabling eradication of leukemic CD34 þ stem/ progenitor cells. Indeed, inhibition of constitutively active FLT3 has been shown to prolong survival in a mouse model of FLT3-ITD þ leukemia (14,15) and several tyrosine kinase inhibitors (TKI) have entered clinical trials (16)(17)(18). However, although inhibition of mutant FLT3 leads to clearance of leukemic blasts in the periphery, the bone marrow often remains unchanged and remissions are usually short-lived (17,19), raising the question whether a protective effect of the marrow niche on LSCs exists.…”

Section: Introductionmentioning

confidence: 99%

Stromal Niche Cells Protect Early Leukemic FLT3-ITD+ Progenitor Cells against First-Generation FLT3 Tyrosine Kinase Inhibitors

et al. 2011

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Targeting constitutively activated FMS-like tyrosine kinase 3 [(FLT3); FLT3-ITD] with tyrosine kinase inhibitor (TKI) in acute myeloid leukemia (AML) leads to clearance of blasts in the periphery but not in the bone marrow, suggesting a protective effect of the marrow niche on leukemic stem cells. In this study, we examined the effect of stromal niche cells on CD34 þ progenitors from patients with FLT3-ITD þ or wild-type FLT3 (FLT3-WT) AML treated with the TKIs SU5614 or sorafenib. TKIs effectively and specifically inhibited FLT3 and increased the fraction of undivided progenitors in both FLT3-ITD þ and FLT3-WT samples. Treatment with SU5614 and sorafenib also reduced the number of mature leukemic progenitors, whereas contact with stroma protected against this cell loss. In contrast, primitive long-term progenitors from both FLT3-ITD þ and FLT3-WT AML were resistant to TKIs. Additional contact with niche cells significantly expanded long-term FLT3-ITD þ but not FLT3-WT progenitors in the presence of SU5614 but not that of sorafenib. Thus, TKIs with first-generation inhibitors fail to eradicate early leukemic stem/progenitor cells in FLT3-ITD þ AML. Further, we defined a specific interaction between FLT3-ITD þ progenitors and niche cells that enables the maintenance of leukemic progenitors in the presence of TKI. Collectively, our findings suggest that molecular therapy may have unpredicted effects on leukemic progenitors, underscoring the necessity of developing strategies to selectively eliminate the malignant stem cell clone. Cancer Res; 71(13); 4696-706. Ó2011 AACR.

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A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia

Cited by 241 publications

References 15 publications

Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML

Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML

Potential autocrine function of vascular endothelial growth factor in head and neck cancer via vascular endothelial growth factor receptor-2

Stromal Niche Cells Protect Early Leukemic FLT3-ITD+ Progenitor Cells against First-Generation FLT3 Tyrosine Kinase Inhibitors

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