Abstract
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-d]pyrimidine derivative, selected for its favorable activity against SRC, was tested in vitro and in vivo on glioblastoma cell lines. In vivo, 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 in vitro 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. Mol Cancer Ther; 15(7); 1535-44. ©2016 AACR.
Highlights
Glioblastoma is the most frequent primary brain tumor in adults
In vitro antiproliferative effect of Si306 on glioblastoma cells We initially tested Si306 in two different human glioblastoma astrocytoma cell lines, U-87 MG and U-251
We observed that SRC inhibition induced the down-modulation of the active form of b-platelet-derived growth factor receptor (PDGFR)
Summary
Glioblastoma is the most frequent primary brain tumor in adults. Glioblastoma usually demonstrates very aggressive cellular features, with infiltration of normal brain [1]. Glioblastoma is characterized by increased proliferation and demand of nutrient and oxygen as revealed by frequent evidence of microvascularity and necrosis [2]. The prognosis of glioblastoma is poor: median survival time is less than one year since the diagnosis and patients usually die within two years [3]. In presence of aggressive standard therapy, that is, surgical resection, followed by concomitant radiotherapy and temozolomide therapy, fatal relapses could not be avoided. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/)
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