A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease

Fiedler, Walter; Serve, Hubert; Döhner, Hartmut; Schwittay, Michael; Ottmann, Oliver G.; O’Farrell, Anne-Marie; Bello, Carlo L.; Allred, Randy; Manning, William C.; Cherrington, Julie M.; Louie, Sharianne G.; Hong, Weiru; Brega, Nicoletta; Massimini, Giorgio; Scigalla, P.; Berdel, Wolfgang E.; Hossfeld, Dieter K.

doi:10.1182/blood-2004-05-1846

Cited by 457 publications

(283 citation statements)

References 30 publications

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“…Several trials combining TKI and conventional chemotherapy are ongoing in patients with newly diagnosed FLT3-mutant AML or in AML in relapse. [221][222][223][224][225][226][227][228][229] TKI may also target c-KIT mutations, although in such cases the exact location and nature of the mutation must be determined individually because specific inhibitors are active against particular c-KIT mutations. For example, cells carrying insertion/deletion in exon 8, ITD of exon 11 and 12 or substitutions at codon 822 are sensitive to imatinib, while D816 mutations confer a resistance to imatinib but can be targeted with other TKI such as midostaurin, nilotinib or dasatinib.…”

Section: Gene Mutations As Potential Therapeutic Targetsmentioning

confidence: 99%

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

et al. 2008

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Acute myeloid leukemia (AML) is a heterogeneous group of neoplastic disorders with great variability in clinical course and response to therapy, as well as in the genetic and molecular basis of the pathology. Major advances in the understanding of leukemogenesis have been made by the characterization and the study of acquired cytogenetic abnormalities, particularly reciprocal translocations observed in AML. Besides these major cytogenetic abnormalities, gene mutations also constitute key events in AML pathogenesis. In this review, we describe the contribution of known gene mutations to the understanding of AML pathogenesis and their clinical significance. To gain more insight in this understanding, we clustered these alterations in three groups: (1) mutations affecting genes that contribute to cell proliferation (FLT3, c-KIT, RAS, protein tyrosine standard phosphatase nonreceptor 11); (2) mutations affecting genes involved in myeloid differentiation (AML1 and CEBPA) and (3) mutations affecting genes implicated in cell cycle regulation or apoptosis (P53, NPM1). This nonexhaustive review aims to show how gene mutations interact with each other, how they contribute to refine prognosis and how they can be useful for risk-adapted therapeutic management of AML patients.

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Section: Gene Mutations As Potential Therapeutic Targetsmentioning

confidence: 99%

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

et al. 2008

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“…Expression of Mcl-1 is upregulated at the transcriptional level by STAT5, PI3K/Akt and Mek/Erk pathways [11][12][13] and at the posttranslational level by the PI3K/ Akt pathway. 14 It has been reported that FLT3 inhibition induces apoptosis in leukemic blasts of AML patients who carry the FLT3 mutation, [15][16][17][18][19][20][21] though the mechanism remains unknown. Several FLT3 inhibitors have been developed, including sorafenib (BAY43-9006), lestaurtinib (CEP-701), PKC412, sunitinib (SU11248) and tandutinib (MLN-518), but clinical trials using these inhibitors as single agents have not been successful.…”

Section: Introductionmentioning

confidence: 99%

“…Several FLT3 inhibitors have been developed, including sorafenib (BAY43-9006), lestaurtinib (CEP-701), PKC412, sunitinib (SU11248) and tandutinib (MLN-518), but clinical trials using these inhibitors as single agents have not been successful. [17][18][19][20][21] Conventional chemotherapy in combination with FLT3 inhibitors has therefore emerged as the preferred therapeutic strategy in the current phase 3 trials. [17][18][19] It is conceivable that targeting multiple arms of the apoptotic regulatory machinery with FLT3 inhibition would be more efficacious than targeting the mutated FLT3 alone.…”

Section: Introductionmentioning

confidence: 99%

Selective FLT3 inhibitor FI-700 neutralizes Mcl-1 and enhances p53-mediated apoptosis in AML cells with activating mutations of FLT3 through Mcl-1/Noxa axis

et al. 2009

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Treatment using Fms-like tyrosine kinase-3 (FLT3) inhibitors is a promising approach to overcome the dismal prognosis of acute myeloid leukemia (AML) with activating FLT3 mutations. Current trials are combining FLT3 inhibitors with p53-activating conventional chemotherapy. The mechanisms of cytotoxicity of FLT3 inhibitors are poorly understood. We investigated the interaction of FLT3 and p53 pathways after their simultaneous blockade using the selective FLT3 inhibitor FI-700 and the MDM2 inhibitor Nutlin-3 in AML. We found that FI-700 immediately reduced antiapoptotic Mcl-1 levels and enhanced Nutlininduced p53-mediated mitochondrial apoptosis in FLT3/internal tandem duplication cells through the Mcl-1/Noxa axis. FI-700 induced proteasome-mediated degradation of Mcl-1, resulting in the reduced ability of Mcl-1 to sequester proapoptotic Bim. Nutlin-3 induced Noxa, which displaced Bim from Mcl-1. The FI-700/Nutlin-3 combination profoundly activated Bax and induced apoptosis. Our findings suggest that FI-700 actively enhances p53 signaling toward mitochondrial apoptosis and that a combination strategy aimed at inhibiting FLT3 and activating p53 signaling could potentially be effective in AML.

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“…In a Phase I trial, KW-2449 treatment led to transient decreases in peripheral blast counts (Cortes et al, 2008;Pratz and Levis, 2008;Pratz et al, 2009 (Fiedler et al, 2005;Kancha et al, 2007;O'Farrell et al, 2003a, b), as well as the piperazinyl quinazoline MLN518 (tandutinib; CT53518; Millennium, Cambridge, MA, USA) (Kelly et al, 2002b;Cheng and Paz, 2008). There is presently an ongoing Phase I/II trial investigating SU11248 combined with standard chemotherapy in mutant FLT3-positive AML patients over the age of 60 years.…”

Section: Kinase Inhibitors Under Clinical Investigation For Mutant Flmentioning

confidence: 99%

Drug resistance in mutant FLT3-positive AML

et al. 2010

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Mutant Fms-Like Tyrosine kinase-3 (FLT3), which is expressed in the leukemic cells of a subpopulation of acute myeloid leukemia (AML) patients, represents an attractive target for the therapy of AML. There are several FLT3 inhibitors presently in clinical trials with sufficient efficacy and toxicity features to warrant further testing in combination with standard therapies. However, the transient and partial responses observed in AML patients treated with FLT3 inhibitors, coupled with the discovery of drug-resistant leukemic blast cells in AML patients, have made resistance to FLT3 inhibitors a growing concern. In this study, we provide an overview of the role of mutant FLT3 in AML, FLT3 inhibitors under clinical and preclinical investigation, mechanisms of resistance to FLT3 inhibitors, and possible therapeutic approaches to overcoming this resistance.

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A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease

Cited by 457 publications

References 30 publications

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

Selective FLT3 inhibitor FI-700 neutralizes Mcl-1 and enhances p53-mediated apoptosis in AML cells with activating mutations of FLT3 through Mcl-1/Noxa axis

Drug resistance in mutant FLT3-positive AML

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