Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics

DeAngelo, Daniel J.; Stone, Richard; Heaney, Mark L.; Nimer, Stephen D.; Paquette, Ronald; Klisovic, Rebecca B.; Caligiuri, Michael A.; Cooper, Michael R.; Lecerf, Jean; Karol, Michael D.; Sheng, Shihong; Holford, Nicholas H. G.; Curtin, Peter T.; Druker, Brian J.; Heinrich, Michael C.

doi:10.1182/blood-2006-02-005702

Cited by 250 publications

(166 citation statements)

References 24 publications

(43 reference statements)

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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%

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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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Section: Introductionmentioning

confidence: 99%

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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“…18,19 Other FLT3 inhibitors showed similar limited efficacy in clinical trials. [20][21][22][23][24] The common strategy for solving this problem is to combine PKC412 with other antileukemic agents. However, to our knowledge, no data have been reported for the cytotoxic interactions of PKC412 with other agents.…”

Section: Introductionmentioning

confidence: 99%

Divergent cytotoxic effects of PKC412 in combination with conventional antileukemic agents in FLT3 mutation-positive versus -negative leukemia cell lines

et al. 2007

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FMS-like tyrosine kinase-3 (FLT3) is a new therapeutic target for acute myelocytic leukemia (AML), because FLT3 mutations are the most common genetic alterations in AML and are directly related to leukemogenesis. We studied cytotoxic interactions of a FLT3 inhibitor, PKC412, with eight conventional antileukemic agents (cytarabine, doxorubicin, idarubicin, mitoxantrone, etoposide, 4-hydroperoxy-cyclophosphamide, methotrexate and vincristine) using three leukemia cell lines carrying FLT3 mutations (MOLM13, MOLM14 and MV4-11) and five leukemia cell lines without FLT3 mutations (KOPB-26, THP-1, BALL-1, KG-1 and U937). PKC412 showed synergistic effects with all agents studied except methotrexate for FLT3-mutated cell lines in isobologram analysis. In contrast, PKC412 was rather antagonistic to most drugs, except for 4-hydroperoxy-cyclophosphamide and vincristine, in leukemia cell lines without FLT3 mutations. Cell-cycle analysis revealed that PKC412 induced G1 arrest in leukemia cell lines carrying FLT3 mutations, whereas it arrested cells in G2/M phase in the absence of FLT3 mutations, which may underlie the divergent cytotoxic interactions. These results suggest that the simultaneous administration of PKC412 and other agents except methotrexate is clinically effective against FLT3 mutationpositive leukemias, whereas it would be of little benefit for FLT3 mutation-negative leukemias. Our findings may be of help for the design of PKC412-based combination chemotherapy.

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“…A phase 2 study in relapsed/refractory patients with FLT3-ITD AML is currently recruiting patients, with interim data supporting doses of quizartinib 135 and 90 mg in men and women, respectively, due to QTc prolongation at a starting dose of 200 mg. 74 Tandutinib (MLN518) Tandutinib is more selective for FLT3 than midostaurin or lestaurtinib, although it does have some activity against plateletderived growth factor receptor-b and c-KIT. 75 Although tandutinib demonstrated some antileukemic activity as a single agent and in combination with chemotherapy in phase 1 studies, 76,77 doselimiting muscle weakness (reversible) and high rates of nausea and vomiting were observed. This may be related to the slow clearance and resultant high plasma levels of the drug.…”

Section: Quizartinib (Ac220)mentioning

confidence: 99%

Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

2012

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Acute myeloid leukemia (AML) is a highly heterogenous disease with multiple signaling pathways contributing to its pathogenesis. A key driver of AML is the FMS-like tyrosine kinase receptor-3 (FLT3). Activating mutations in FLT3, primarily the FLT3-internal tandem duplication (FLT3-ITD), are associated with decreased progression-free and overall survival. Identification of the importance of FLT3-ITD and the FLT3 pathway in the prognosis of patients with AML has stimulated efforts to develop therapeutic inhibitors of FLT3. Although these inhibitors have shown promising antileukemic activity, they have had limited efficacy to date as single agents and may require use in combination with cytotoxic chemotherapies. Here, we review clinical and preclinical results for the clinically mature FLT3 inhibitors currently in development. We conclude that multitargeted FLT3 inhibitors may have more utility earlier in the course of disease, when in vitro evidence suggests that AML cells are less dependent on FLT3 signaling, perhaps because of upregulation of multiple other signaling pathways. More potent agents may have greater utility in relapsed and heavily pretreated patients, in whom high levels of circulating FLT3 ligand may necessitate use of an agent with a very favorable pharmacokinetic/ pharmacodynamic profile. Novel combination regimens are also discussed.

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Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics

Abstract: Tandutinib (MLN518/CT53518

Cited by 250 publications

References 24 publications

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

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

Divergent cytotoxic effects of PKC412 in combination with conventional antileukemic agents in FLT3 mutation-positive versus -negative leukemia cell lines

Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

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