C-kit receptor expression in Ewing's sarcoma: lack of prognostic value but therapeutic targeting opportunities in appropriate conditions.
OBJECTIVE
Autocrine/paracrine stimulation of c-kit has been recently observed in Ewing's sarcoma (ES) cell lines. In this study, we tested the prognostic and therapeutic role of the receptor in this tumor.


METHODS
One hundred one ES tumor biopsies were evaluated for the expression of c-kit by the avidin-biotin-peroxidase procedure. Effectiveness of STI-571 (Gleevec; Novartis, Basel, Switzerland), a selective inhibitor of specific tyrosine kinases, was analyzed with respect to in vitro growth and migration inhibition, as single agent or in combination with doxorubicin.


RESULTS
Approximately 30% of patients expressed c-kit in their primary tumors. No significant association between the expression of the receptor and the clinical outcome was observed. In vitro growth of ES cell lines showing high levels of c-kit demonstrated limited inhibition by exposure to STI-571 (10 micromol/L is required to obtain 40% to 50% of growth inhibition). A decrease of stem-cell factor-mediated ES cell migration was also found. The drug acted additively with doxorubicin in inhibiting ES cell growth.


CONCLUSIONS
The negative prognostic findings and the limited in vitro therapeutic activity of STI-571 indicate that the putative aberrant signaling provided by c-kit overexpression may be dispensable for ES development and unlikely to constitute a critical therapeutic target. Accordingly, the dose of STI-571 required to give a significant ES growth inhibition is much higher than for those tumors in which mutations of c-kit constitute a relevant pathogenetic event. Nevertheless, in the subset of ES patients showing a high level of c-kit expression, the activity of the drug may be exploited in combination with standard therapy.
Scotlandi
Katia
K
Laboratorio di Ricerca Oncologica and Servicio di Anatomia Patologica, Istituti Ortopedici Rizzoli, Via Di Barbiano 1/10, 40136 Bologna, Italy. katia.scotlandi@ior.it
Manara
Maria Cristina
MC
Strammiello
Rosaria
R
Landuzzi
Lorena
L
Benini
Stefania
S
Perdichizzi
Stefania
S
Serra
Massimo
M
Astolfi
Alessia
A
Nicoletti
Giordano
G
Lollini
Pier-Luigi
PL
Bertoni
Franco
F
Nanni
Patrizia
P
Picci
Piero
P
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001859:Bone Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002648:Child; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D012512:Sarcoma, Ewing / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D001549:Benzamides; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D004317:Doxorubicin; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit