Trimodal Glioblastoma Treatment Consisting of Concurrent Radiotherapy, Temozolomide, and the Novel TGF-β Receptor I Kinase Inhibitor LY2109761

• DOI: 10.1593/neo.11258
• Publication Date: 2015-04-23T13:11:07Z
• Authors: Mengxian Zhang; Tobias W. Herion; Carmen Timke; Na Han; Kai Hauser; Klaus J. Weber; Peter Peschke; Ute Wirkner; Michael Lahn; Peter E. Huber
• Keywords: Temozolomide; U87; Clonogenic assay; CD31

Here we investigate the effects of novel transforming growth factor-β receptor I (TGF-βRI) serine/threonine kinase inhibitor LY2109761 on glioblastoma when combined with present clinical standard combination regimen radiotherapy and temozolomide (TMZ). Human GBM U87 (methylated MGMT promoter), T98 (unmethylated endothelial cells (HUVECs) were treated combinations LY2109761, TMZ, radiation. We found that reduced clonogenic survival further enhanced radiation-induced anticlonogenicity. In addition, had antimigratory antiangiogenic in Matrigel migration tube formation assays. vivo, human xenograft tumors growing subcutaneously BALB/c nu/nu mice, delayed tumor alone fractionated radiation TMZ. Interestingly, as expected, methylated model was more sensitive to TMZ than unmethylated all experiments, whereas opposite for LY2109761. Moreover, respect angiogenesis, while decreased proliferation index (Ki-67) microvessel density (CD31 count), relative pericyte coverage (α-SMA/CD31 ratio) increased particular after triple therapy, suggesting a vascular normalization effect induced by This could be attributed part decrease Ang-2/Ang-1 messenger RNA ratio. also blood perfusion quantified noninvasive dynamic contrast-enhanced magnetic resonance imaging. Together, data indicate addition TGF-βRI (radiation plus TMZ) has potential improve outcome glioblastoma, especially patients promoter status.