Synergistic Antitumor Effect between Gefitinib and Fractionated Irradiation in Anaplastic Oligodendrogliomas Cannot Be Predicted by the Egfr Signaling ActivityReport as inadecuate




Synergistic Antitumor Effect between Gefitinib and Fractionated Irradiation in Anaplastic Oligodendrogliomas Cannot Be Predicted by the Egfr Signaling Activity - Download this document for free, or read online. Document in PDF available to download.

In high-grade gliomas, the identification of patients that could benefit from EGFR inhibitors remains a challenge, hindering the use of these agents. Using xenografts models, we evaluated the antitumor effect of the combined treatment -gefitinib + radiotherapy- and aimed to identify the profile of responsive tumors. Expression of phosphorylated proteins involved in the EGFR-dependent signaling pathways was analyzed in 10 glioma models. We focused on three models of anaplastic oligodendrogliomas TCG2, TCG3 and TCG4 harboring high levels of phospho-EGFR, phospho-AKT and phospho-MEK1. They were treated with gefitinib GEF 75 mg-kg-day x 5 days-week, for 2 weeks and-or fractionated radiotherapy RT: 5x2Gy-week for 2 weeks. Our results showed that GEF and-or RT induced significant tumor growth delays. However, only the TCG3 xenografts were highly responsive to the combination GEF+RT, with ∼50% of tumor cure. Phosphoproteins analysis five days after treatment onset demonstrated in TCG3 xenografts, but not in TCG2 model, that the EGFR-dependent pathways were inhibited after GEF treatment. Moreover, TCG3-bearing mice receiving GEF monotherapy exhibited a transient beneficial therapeutic response, rapidly followed by tumor regrowth, along with a major vascular remodeling. Taken together, our data evoked an -EGFR-addictive- behavior for TCG3 tumors. This study confirms that combination of gefitinib with fractionated irradiation could be a potent therapeutic strategy for anaplastic oligodendrogliomas harboring EGFR abnormalities but this treatment seems mainly beneficial for -EGFR-addictive- tumors. Unfortunately, neither the usual molecular markers EGFR amplification, PTEN loss nor the basal overexpression of phosphoproteins were useful to distinguish this responsive tumor. Evaluating the impact of TKIs on the EGFR-dependent pathways during the treatment might be more relevant, and requires further validation.



Author: Sophie Pinel , Jihane Mriouah, Marc Vandamme, Alicia Chateau, François Plénat, Eric Guérin, Luc Taillandier, Valérie Bernier-

Source: http://plos.srce.hr/



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