Data from Suppression of SRC Signaling Is Effective in Reducing Synergy between Glioblastoma and Stromal Cells

Abstract

<div>Abstract<p>Glioblastoma cells efficiently interact with and infiltrate the surrounding normal tissue, rendering surgical resection and adjuvant chemo/radiotherapy ineffective. New therapeutic targets, able to interfere with glioblastoma's capacity to synergize with normal brain tissue, are currently under investigation. The compound Si306, a pyrazolo[3,4-<i>d</i>]pyrimidine derivative, selected for its favorable activity against SRC, was tested <i>in vitro</i> and <i>in vivo</i> on glioblastoma cell lines. <i>In vivo</i>, combination treatment with Si306 and radiotherapy was strongly active in reducing U-87 xenograft growth with respect to control and single treatments. The histology revealed a significant difference in the stromal compartment of tumoral tissue derived from control or radiotherapy-treated samples with respect to Si306-treated samples, showing in the latter a reduced presence of collagen and α-SMA–positive cells. This effect was paralleled <i>in vitro</i> by the capacity of Si306 to interfere with myofibroblastic differentiation of normal fibroblasts induced by U-87 cells. In the presence of Si306, TGF-β released by U-87 cells, mainly in hypoxia, was ineffective in upregulating α-SMA and β-PDGFR in fibroblasts. Si306 efficiently reached the brain and significantly prolonged the survival of mice orthotopically injected with U-87 cells. Drugs that target SRC could represent an effective therapeutic strategy in glioblastoma, able to block positive paracrine loop with stromal cells based on the β-PDGFR axis and the formation of a tumor-promoting microenvironment. This approach could be important in combination with conventional treatments in the effort to reduce tumor resistance to therapy. <i>Mol Cancer Ther; 15(7); 1535–44. ©2016 AACR</i>.</p></div>