Clinical and molecular evidence for c-kit receptor as a therapeutic target in neuroblastic tumors

Stefania Uccini, Olga Mannarino, Heather P. McDowell, Ursula Pauser, Roberta Vitali, Pier Giorgio Natali, Pierluigi Altavista, Tiziana Andreano, Simona Coco, Renata Boldrini, Sandro Bosco, Anna Clerico, Denis Cozzi, Alberto Donfrancesco, Alessandro Inserra, George Kokai, Paul D. Losty, Maria R. Nicotra, Giuseppe Raschellà, Gian Paolo ToniniCarlo Dominici

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Abstract

Purpose: Clinicobiological characteristics of neuroblastic tumor (NT) expressing c-kit tyrosine kinase receptor and/or its ligand, stem cell factor (SCF), are debated. This study aimed at investigating the clinicobiological features of primary NTs expressing c-kit and/or SCF in order to define the clinical relevance of selective therapeutic targeting. Experimental Design: c-Kit and SCF expression was studied in 168 NTs using immunohistochemistry and in 106 of 168 using Northern blot. Quantitative determination of c-kit expression in 54 additional NTs was also done using real-time reverse transcription-PCR. Correlations between c-kit and SCF expression and clinicobiological features were analyzed using χ 2 test, univariate, and multivariate regression analyses. Results: c-Kit protein was detected in 21 of 168 NTs (13%) and its mRNA in 23 of 106 NTs (22%). SCF protein was shown in 30 of 106 NTs (28%) and its mRNA in 33 of 106 NTs (31%). No mutations in exon 11 of c-kit gene were identified. By univariate analysis, c-kit and SCF expression correlated with advanced stage, MYCN amplification, and 1p36 allelic loss. Cox simple regression analysis showed that overall survival probability was 17% in the c-kit-positive subset versus 68% in the negative (P <0.001), 43% in the SCF-positive subset versus 78% in the negative (P <0.001). When using real-time reverse transcription-PCR, significant levels of c-kit mRNA were found in 35 of 54 NTs (65%), but the correlations with clinicobiological features were no longer documented. Conclusions: c-Kit expression can be detected in the majority of primary NTs. High levels of expression are preferentially found in tumors with unfavorable clinicobiological variables. c-Kit may represent a useful therapeutic target in a subset of otherwise untreatable NTs.

Original languageEnglish
Pages (from-to)380-389
Number of pages10
JournalClinical Cancer Research
Volume11
Issue number1
Publication statusPublished - Jan 1 2005

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Uccini, S., Mannarino, O., McDowell, H. P., Pauser, U., Vitali, R., Natali, P. G., Altavista, P., Andreano, T., Coco, S., Boldrini, R., Bosco, S., Clerico, A., Cozzi, D., Donfrancesco, A., Inserra, A., Kokai, G., Losty, P. D., Nicotra, M. R., Raschellà, G., ... Dominici, C. (2005). Clinical and molecular evidence for c-kit receptor as a therapeutic target in neuroblastic tumors. Clinical Cancer Research, 11(1), 380-389.