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C-kit receptor expression in Ewing's sarcoma: lack of prognostic value but therapeutic targeting opportunities in appropriate conditions.
J Clin Oncol. 2003 May 15; 21(10):1952-60.JC

Abstract

PURPOSE

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.

CONCLUSION

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.

Authors+Show Affiliations

Laboratorio di Ricerca Oncologica and Servicio di Anatomia Patologica, Istituti Ortopedici Rizzoli, Via Di Barbiano 1/10, 40136 Bologna, Italy. katia.scotlandi@ior.itNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12743148

Citation

Scotlandi, Katia, et al. "C-kit Receptor Expression in Ewing's Sarcoma: Lack of Prognostic Value but Therapeutic Targeting Opportunities in Appropriate Conditions." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, vol. 21, no. 10, 2003, pp. 1952-60.
Scotlandi K, Manara MC, Strammiello R, et al. C-kit receptor expression in Ewing's sarcoma: lack of prognostic value but therapeutic targeting opportunities in appropriate conditions. J Clin Oncol. 2003;21(10):1952-60.
Scotlandi, K., Manara, M. C., Strammiello, R., Landuzzi, L., Benini, S., Perdichizzi, S., Serra, M., Astolfi, A., Nicoletti, G., Lollini, P. L., Bertoni, F., Nanni, P., & Picci, P. (2003). C-kit receptor expression in Ewing's sarcoma: lack of prognostic value but therapeutic targeting opportunities in appropriate conditions. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 21(10), 1952-60.
Scotlandi K, et al. C-kit Receptor Expression in Ewing's Sarcoma: Lack of Prognostic Value but Therapeutic Targeting Opportunities in Appropriate Conditions. J Clin Oncol. 2003 May 15;21(10):1952-60. PubMed PMID: 12743148.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - C-kit receptor expression in Ewing's sarcoma: lack of prognostic value but therapeutic targeting opportunities in appropriate conditions. AU - Scotlandi,Katia, AU - Manara,Maria Cristina, AU - Strammiello,Rosaria, AU - Landuzzi,Lorena, AU - Benini,Stefania, AU - Perdichizzi,Stefania, AU - Serra,Massimo, AU - Astolfi,Alessia, AU - Nicoletti,Giordano, AU - Lollini,Pier-Luigi, AU - Bertoni,Franco, AU - Nanni,Patrizia, AU - Picci,Piero, PY - 2003/5/14/pubmed PY - 2003/5/28/medline PY - 2003/5/14/entrez SP - 1952 EP - 60 JF - Journal of clinical oncology : official journal of the American Society of Clinical Oncology JO - J. Clin. Oncol. VL - 21 IS - 10 N2 - PURPOSE: 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. CONCLUSION: 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. SN - 0732-183X UR - https://www.unboundmedicine.com/medline/citation/12743148/C_kit_receptor_expression_in_Ewing's_sarcoma:_lack_of_prognostic_value_but_therapeutic_targeting_opportunities_in_appropriate_conditions_ L2 - http://ascopubs.org/doi/full/10.1200/JCO.2003.11.111?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -