Target-driven exploratory study of imatinib mesylate in children with solid malignancies by the Innovative Therapies for Children with Cancer (ITCC) European Consortium

Geoerger, Birgit; Morland, Bruce; Ndiaye, Anna Julienne Selbé; Doz, François; Kalifa, G.; Geoffray, A.; Pichon, F.; Frappaz, Didier; Chatelut, Étienne; Opolon, Paule; Hain, Sharon F.; Boderet, Francoise; Bosq, Jacques; Émile, Jean-François; Deley, Marie-Cécile Le; Capdeville, Renaud; Vassal, Gilles

doi:10.1016/j.ejca.2009.03.007

Cited by 55 publications

(32 citation statements)

References 33 publications

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“…Two children with AT/RTs who had been stratified for imatinib treatment based on PDGF receptor expression status experienced progressive Original Article disease. 19 In that study, the expression of c-Abl had not been evaluated. As in our study variations in the quantity of c-Abl-positive cells in rhabdoid tumor samples were not correlated with PDGF receptor expression, stratification for PDGF receptor expression may not be sufficient in rhabdoid tumors.…”

Section: Discussionmentioning

confidence: 99%

“…[9][10][11][12][13][14][15][16] Imatinib, a tyrosine kinase inhibitor directed against c-Abl, c-Kit and platelet-derived growth factor (PDGF) receptor subtypes a and b, 17 reportedly is tolerated relatively well in children. 18,19 Because it has been demonstrated that imatinib inhibits proliferation of the rhabdoid tumor cell line BT12, 20 our objective was to investigate the expression and functional role of tyrosine kinases targeted by imatinib in rhabdoid tumors.…”

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confidence: 99%

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The tyrosine kinase c‐Abl promotes proliferation and is expressed in atypical teratoid and malignant rhabdoid tumors

Koos

Jeibmann

Lünenbürger

et al. 2010

Cancer

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BACKGROUND: Atypical teratoid/rhaboid tumors (AT/RTs) and extracranial malignant rhabdoid tumors are highly malignant neoplasms with a dismal prognosis. These tumors predominantly affect infants and targeted, adjuvant treatment approaches would be highly desirable. METHODS: In the current study, the authors investigated the expression and functional role of tyrosine kinases in 2 malignant rhabdoid tumor cell lines (A204 and G401) and in a series of 5 AT/RTs and 18 malignant rhabdoid tumors (13 rhabdoid tumors of the kidney and 5 extrarenal rhabdoid tumors). RESULTS: Both cell lines consistently expressed the tyrosine kinase c-Abl, which promoted proliferation as assessed by small interfering RNA knockdown. Blockage of c-Abl using the tyrosine kinase inhibitor imatinib resulted in reduced cellular growth in both cell lines. Furthermore, c-Abl was expressed in all rhabdoid tumors, whereas expression of platelet-derived growth factor receptor subtypes alpha and beta was infrequent and c-Kit expression was absent. CONCLUSIONS: The current data pointed toward a role for c-Abl in the biology of malignant rhabdoid tumors and provided a rationale for the investigation of tyrosine kinase inhibitors that target c-Abl for the treatment of these aggressive tumors. Cancer 2010;116:5075-81.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The tyrosine kinase c‐Abl promotes proliferation and is expressed in atypical teratoid and malignant rhabdoid tumors

Koos

Jeibmann

Lünenbürger

et al. 2010

Cancer

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“…To date, the efficacy and side effects of imatinib have been evaluated in controlled phase I/II trials comprising less than 200 children with Phϩ leukemias and solid tumors. [22][23][24][25][26][27][28][29][30] Doses of 260 to 340 mg/m 2 give drug exposures similar to the 400 to 600 mg adult dosage levels; therefore, the starting dose in children should be 300 mg/m 2 orally once daily (maximum absolute dose, 400 mg). The recommended pediatric doses for CML-AP are 400 mg/m 2 daily (maximum absolute dose, 600 mg) and for CML-BP 500 mg/m 2 daily (maximum absolute dose, 800 mg).…”

Section: Treatment With Tkismentioning

confidence: 99%

“…33,34 So far, it can be deduced from small cohorts that side effects occur with the same or even a lower frequency and are less severe than in adults. 23,26,28 Toxicity includes nausea, vomiting, diarrhea, skin rash, edema, elevated liver enzymes (mild transaminitis generally occurs early in the course of treatment), and cytopenias. Especially in the beginning of therapy or when advanced stages of CML are treated, the onset of cytopenias may require short treatment interruptions because of an inadequate reservoir of normal stem cells.…”

Section: Side Effects Of Imatinibmentioning

confidence: 99%

Treatment of Pediatric Chronic Myeloid Leukemia in the Year 2010: Use of Tyrosine Kinase Inhibitors and Stem-Cell Transplantation

Suttorp

Millot²

2010

Hematology

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Allogeneic hematopoietic stem cell transplantation (allo-SCT) remains the only proven cure for chronic myeloid leukemia (CML), a rare malignancy in childhood. With the excellent results induced by the tyrosine kinase inhibitor (TKI) imatinib in adults in the last decade, the appropriate management of children with CML has also changed radically, and only a minority are now transplanted as a front-line treatment. Data on pediatric experiences with imatinib in CML from controlled trials remain very limited, but this review of available data describes the role of imatinib in children with CML, addressing: 1) the starting dose; 2) pharmacokinetics in childhood; 3) possible adverse effects, with a focus on the still-growing skeleton; 4) early monitoring of treatment efficacy in an attempt to avoid failure; 5) the timing of allo-SCT in children; and 6) treatment of CML relapse after allo-SCT. Because the characteristics of CML in children seem to overlap extensively with what is described in adult internal medicine, most answers and pediatric algorithms are adapted from the treatment of CML in adults. Today in 2010, allo-SCT in children should be postponed until CML becomes refractory to imatinib. The approach for young patients with suboptimal responses is unclear because data on the efficacy and safety of second-generation TKIs in childhood are almost entirely missing. Other than being included in a formal trial on second-generation TKIs, allo-SCT for patients failing imatinib remains the first choice.

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“…PI3K, by combinations of imatinib with hydroxyurea, are currently underway (7). So far the responses observed in clinical studies using imatinib in malignant glioma have been too few to allow the identification of reliable and reproducible biomarkers for predicting response and survival (5,(17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

Selective inhibition of PDGFR by imatinib elicits the sustained activation of ERK and downstream receptor signaling in malignant glioma cells

Dong

Jia²,

Wang³

et al. 2011

Int J Oncol

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Abstract. Clinical studies using the tyrosine kinase inhibitor, imatinib mesylate (Gleevec ® ), in glioblastoma, have shown no major inhibition of tumor growth or extension of survival for patients, unlike those in chronic myeloid leukemia (CML) and gastrointestinal stromal tumors. The molecular mechanisms of action of imatinib in glioblastoma cells are still not well understood. In this study, we investigated the effects of imatinib on the platelet derived growth factor receptor (PDGFR) downstream signaling pathways as well as on other cellular functions in human glioblastoma cells. NIH3T3 fibroblast and K562 CML cells were used for comparison. Western blot analysis demonstrated that imatinib was more effective in inhibiting the activated rather than the quiescent forms of the target proteins. Furthermore, the imatinib treatment induced the sustained activation of extracellular signalregulated kinase (ERK 1/2) signaling as well as components of other downstream signaling pathways, such as PI3K/Akt, STAT3 and p38MAPK. Prior stimulation of the malignant cells with exogenous PDGF-BB partially abrogated this activation. Further analysis indicated that the activation of ERK induced by the imatinib treatment was related to the S-phase re-entry of the cell cycle in one of the three glioma cells. Imatinib significantly inhibited cell migration but not cell growth. The combination treatment of imatinib with a MEK or PI3K inhibitor resulted in significant growth inhibition but did not inhibit cell migration beyond the inhibition achieved with the imatinib treatment alone. The treatment of glioma cells with small interfering RNA inhibiting PDGFRB, however, evoked enhanced Akt signaling. These results indicate that the imatinib treatment of malignant glioma does not result in significant inhibitory effects and should be used with caution.

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Target-driven exploratory study of imatinib mesylate in children with solid malignancies by the Innovative Therapies for Children with Cancer (ITCC) European Consortium

Cited by 55 publications

References 33 publications

The tyrosine kinase c‐Abl promotes proliferation and is expressed in atypical teratoid and malignant rhabdoid tumors

The tyrosine kinase c‐Abl promotes proliferation and is expressed in atypical teratoid and malignant rhabdoid tumors

Treatment of Pediatric Chronic Myeloid Leukemia in the Year 2010: Use of Tyrosine Kinase Inhibitors and Stem-Cell Transplantation

Selective inhibition of PDGFR by imatinib elicits the sustained activation of ERK and downstream receptor signaling in malignant glioma cells

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