Chemical catalogs hibitor of PDGFR, FLT3, and c KIT tyrosine kinase activity. Although no preclinical data have been reported for tandutinib in glioblastoma, 2 early phase trials are assessing tandutinib in recurrent or progressive glioblastoma as monotherapy or combined with bevacizumab. Although gene expression and preclinical data suggest that PDGFR may be a promising target for treating glioblastoma, the available clinical data suggest otherwise. Trial data are awaited from novel combination regimens involving PDGFR inhibitors. Integrins Integrins play key roles regulating cellular adhesion, migration, and invasion. In addition to a structural role, integrins also activate intracellular signaling proteins, including SRC. In various tumors, integrins have an established role in metastasis and angiogenesis.74 Therefore, targeting integrin function may have potential for treating glioblastoma. Cilengitide is a specific aV integrin inhibitor in clinical development. In vitro, cilengitide blocked glioma cell adhesion without effecting drug screening libraries tumor radiosensitivity, despite increasing radiation induced vascular endothelial cell death. However, cilengitide combined with radiotherapy in vivo more than doubled the median duration of survival time to.110 days, compared with radiotherapy alone.
A second study showed inconsistent sodium channel effects of cilengitide on cell migration or invasiveness across several glioma cell lines, although additive effects were observed for cilengitide combined with TMZ.76 Cilengitide has been assessed in clinical trials. In a phase I/IIa trial, cilengitide combined with the current standard of therapy in patients with newly diagnosed glioblastoma was well tolerated, with an encouraging 6 month PFS rate of 69%. Tumor O6 methylguanine DNA methyltransferase promoter methylation predicted a higher likelihood of achieving 6 month PFS, as shown by increases in the durations of PFS and OS to 13.4 months and 23.2 months, respectively, compared with 3.4 and 13.1 months for patients without MGMT promoter methylation. 21 On the basis of these findings, a similar regimen is being compared with radiotherapy/TMZ alone in the phase III CENTRIC trial in patients with newly diagnosed glioblastoma whose naringenin tumors have a hypermethylated MGMT promoter. In a phase IIa study of recurrent glioblastoma, cilengitide monotherapy was well tolerated but was largely inactive, long term disease stabilization was seen in a smaall subset of patients: 10% were progression free for.
Months, and 5% were progression free for.24 months.27 A recent preclinical study has suggested that integrin inhibitors may paradoxically stimulate tumor growth and angiogenesis if doses are missed.77 However, because of the artificial dosing schedule and nonglioma models used for preclinical investigations, this may not represent an issue for ongoing trials in glioblastoma.78 c MET Inhibitors Aberrant signaling by the MET receptors and its ligand, hepatocyte growth factor, has been observed in various tumors, including glioblastoma, and potential involvement in tumorigenesis and metastasis has been reported.79 In a recent study, c MET overexpression was detected in 18 of 62 glioblastoma samples, and patients with c MET overexpression had shorter median survival durations than did those with little.