A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo

Levis, Mark J.; Allebach, Jeffrey; Tse, Kam-Fai; Zheng, Rui; Baldwin, Brenda R.; Smith, B. Douglas; Jones‐Bolin, Susan; Ruggeri, Bruce; Dionne, Craig A.; Small, Donald

doi:10.1182/blood.v99.11.3885

Cited by 432 publications

(408 citation statements)

References 39 publications

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“…18 Subsequently, Smith et al reported results of singleagent CEP-701 in treatment of patients with relapsed or refractory AML. 19 This group utilized an ex vivo bioassay in which cells from a human AML cell line transfected with mutant FLT3 expressing a constitutively phosphorylated FLT3 were incubated with plasma from the patients treated with CEP-701 and then assayed for FLT3 autophosphorylation.…”

Section: Determination Of Levels Of Cep-701 In Prostate Tissuementioning

confidence: 99%

Preclinical and clinical studies with the multi-kinase inhibitor CEP-701 as treatment for prostate cancer demonstrate the inadequacy of PSA response as a primary endpoint

Collins

Carducci

Eisenberger

et al. 2007

Cancer Biology & Therapy

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Purpose-CEP-701 is a potent inhibitor of trk receptors that causes cell death in prostate cancer (PC) models. CEP-701 binds to serum proteins and a preprostatectomy study was performed to assess prostate tissue penetration and clinical response to CEP-701.Methods-Growth assays and Western blot analyses were performed to evaluate CEP-701 kinase inhibition. In a preprostatectomy study, patients received CEP-701 for five days prior to prostatectomy and prostate tissue analyzed for CEP-701 levels. A phase II dose escalation study was performed in patients with hormone refractory PC with rising PSA and no metastases. Endpoints included PSA response and safety.Results-CEP-701 binds to serum proteins limiting tissue penetration. An oral dose of 40 mg bid of CEP-701 for five days produced levels of 219 ± 38 nM in prostate at time of prostatectomy. No patients in the Phase II study met the primary response criteria of >50% PSA decline. Seven/9 patients had increase in PSA slope on CEP-701 compared to PSA slope prestudy. Five/9 patients had a decrease in PSA levels after stopping CEP-701. Laboratory studies showed increased PSA production by CEP-701 growth arrested human PC cells in vitro and in vivo.Conclusions-Evaluation of PSA response is an inadequate indicator of response in CEP-701 treated PC patients. Therefore, the effectiveness of CEP-701 as treatment for prostate cancer has not been adequately tested. Based on a strong preclinical rationale, further clinical studies with CEP-701 using alternative endpoints are indicated.

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Section: Determination Of Levels Of Cep-701 In Prostate Tissuementioning

confidence: 99%

Preclinical and clinical studies with the multi-kinase inhibitor CEP-701 as treatment for prostate cancer demonstrate the inadequacy of PSA response as a primary endpoint

Collins

Carducci

Eisenberger

et al. 2007

Cancer Biology & Therapy

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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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“…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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A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo

Cited by 432 publications

References 39 publications

Preclinical and clinical studies with the multi-kinase inhibitor CEP-701 as treatment for prostate cancer demonstrate the inadequacy of PSA response as a primary endpoint

Preclinical and clinical studies with the multi-kinase inhibitor CEP-701 as treatment for prostate cancer demonstrate the inadequacy of PSA response as a primary endpoint

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

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

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