FLT3 as a therapeutic target in AML: still challenging after all these years

Kindler, Thomas; Lipka, Daniel B.; Fischer, Thomas

doi:10.1182/blood-2010-04-261867

Cited by 328 publications

(302 citation statements)

References 121 publications

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“…These have ultimately shown efficacy only in cutaneous T-cell lymphomas through poorly understood mechanisms (14). Similarly, targeting the activation of FLT3 kinase, a common progression event in many different subtypes of leukemia, failed to yield clinical benefit (15). We cannot rule out that therapeutic intervention on late secondary mutations may have some clinical efficacy, but this possibility remains to be demonstrated with in vivo survival as the endpoint.…”

Section: The Issue Of Target Relevancementioning

confidence: 99%

The Drug-Induced Degradation of Oncoproteins: An Unexpected Achilles' Heel of Cancer Cells?

et al. 2011

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Many targeted therapies against cancer are aimed at inhibiting the enzymatic activity of kinases. Thus far, this approach has undoubtedly yielded significant clinical improvements, but has only rarely achieved cures. Other drugs, which selectively elicit proteasome-dependent degradation of oncoproteins, induce the loss of cancer cell self-renewal and promote cell differentiation and/or apoptosis. In acute promyelocytic leukemia, the cooperative degradation of PML/RARA by arsenic and retinoic acid cures most patients. In this condition and others, drug-induced proteolysis of oncoproteins is feasible and underlies improved clinical outcome. Several transcription factors, nuclear receptors, or fusion proteins driving cancer growth could be candidates for proteolysis-based drug-discovery programs. Summary: Some cancer therapies may degrade oncoproteins. Loss of the driver oncoprotein is associated with loss of cancer cell self-renewal. Leukemia- or sarcoma-associated fusion proteins are the best candidates for small-molecule screens aimed at initiating oncoprotein degradation. Cancer Discovery; 1(2). 117–27. ©2011 AACR.

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Section: The Issue Of Target Relevancementioning

confidence: 99%

The Drug-Induced Degradation of Oncoproteins: An Unexpected Achilles' Heel of Cancer Cells?

et al. 2011

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“…1 In patients with normal karyotype AML, mutations in the FMS-like tyrosine kinase 3 (FLT3) gene represent one of the most frequently observed genetic alterations. About 20-25% of young patients with AML show specific in-frame internal tandem duplications of 3-400 bp in various domains of the FLT3 kinase receptor (FLT3-ITD) gene, leading to a constitutive activation of FLT3 and aberrant activation of multiple downstream signaling pathways (reviewed by Kindler et al 2 ). FLT3-ITD is significantly associated with a poor outcome.…”

Section: Introductionmentioning

confidence: 99%

“…6,7 Accordingly, various FLT3 inhibitors have been tested in clinical trials, both as monotherapy or in combination with chemotherapy. 2 It was shown that FLT3 inhibitors were only marginally effective in unselected AML, whereas responses were more frequently observed in patients harboring mutant FLT3. [8][9][10] For example, in the first phase I trial, testing the FLT3 inhibitor sorafenib (Nexavar, formerly BAY 43-9006) in AML only FLT3-ITD-positive (FLT3-ITD), but not FLT3-ITD-negative AML patients responded.…”

Section: Introductionmentioning

confidence: 99%

High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses

et al. 2012

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Preliminary evidence suggests that the multikinase inhibitor sorafenib has clinical activity in FLT3-ITD-positive (FLT3-ITD) acute myeloid leukemia (AML). However, the quality and sustainability of achievable remissions and clinical variables that influence the outcome of sorafenib monotherapy are largely undefined. To address these questions, we evaluated sorafenib monotherapy in 65 FLT3-ITD AML patients treated at 23 centers. All but two patients had relapsed or were chemotherapy-refractory after a median of three prior chemotherapy cycles. Twenty-nine patients (45%) had undergone prior allogeneic stem cell transplantation (allo-SCT). The documented best responses were: hematological remission in 24 patients (37%), bone marrow remission in 5 patients (8%), complete remission (with and without normalization of peripheral blood counts) in 15 patients (23%) and molecular remission with undetectable FLT3-ITD mRNA in 10 patients (15%), respectively. Seventeen of the patients without prior allo-SCT (47%) developed sorafenib resistance after a median treatment duration of 136 days (range, 56-270 days). In contrast, allo-SCT patients developed sorafenib resistance less frequently (38%) and significantly later (197 days, range 38-225 days; P ¼ 0.03). Sustained remissions were seen exclusively in the allo-SCT cohort. Thus, sorafenib monotherapy has significant activity in FLT3-ITD AML and may synergize with allogeneic immune effects to induce durable remissions.

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“…Others such as c-Raf, b-Raf, c-Kit and Flt3 are also key members of critical pathways for cell proliferation, differentiation and apoptosis (Kemmer et al, 2004;Kindler et al, 2010;Maurer et al, 2011;Berk et al, 2013). Sorafenib may have anti-tumor activities through a dual mechanism, acting indirectly on the tumor angiogenesis via VEGFR/PDGFR pathways and directly on tumor growth by inhibition Raf/Kit/Flt3 signaling (Wilhelm et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Sorafenib for Advanced Non-Small Cell Lung Cancer: a Meta-analysis of Randomized Controlled Trials

Wang

Tang²,

Xie³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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FLT3 as a therapeutic target in AML: still challenging after all these years

Cited by 328 publications

References 121 publications

The Drug-Induced Degradation of Oncoproteins: An Unexpected Achilles' Heel of Cancer Cells?

The Drug-Induced Degradation of Oncoproteins: An Unexpected Achilles' Heel of Cancer Cells?

High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses

Efficacy and Safety of Sorafenib for Advanced Non-Small Cell Lung Cancer: a Meta-analysis of Randomized Controlled Trials

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