Effects of Dual Targeting of Tumor Cells and Stroma in Human Glioblastoma Xenografts with a Tyrosine Kinase Inhibitor against c-MET and VEGFR2

Abstract

Anti-angiogenic treatment of glioblastoma with Vascular Endothelial Growth Factor (VEGF)- or VEGF Receptor 2 (VEGFR2) inhibitors normalizes tumor vessels, resulting in a profound radiologic response and improved quality of life. This approach however does not halt tumor progression by diffuse infiltration, as this phenotype is less angiogenesis dependent. Combined inhibition of angiogenesis and diffuse infiltrative growth would therefore be a more effective treatment approach in these tumors. The HGF/c-MET axis is important in both angiogenesis and cell migration in several tumor types including glioma. We therefore analyzed the effects of the c-MET- and VEGFR2 tyrosine kinase inhibitor cabozantinib (XL184, Exelixis) on c-MET positive orthotopic E98 glioblastoma xenografts, which routinely present with angiogenesis-dependent areas of tumor growth, as well as diffuse infiltrative growth. In in vitro cultures of E98 cells, cabozantinib effectively inhibited c-MET phosphorylation, concomitant with inhibitory effects on AKT and ERK1/2 phosphorylation, and cell proliferation and migration. VEGFR2 activation in endothelial cells was also effectively inhibited in vitro. Treatment of BALB/c nu/nu mice carrying orthotopic E98 xenografts resulted in a significant increase in overall survival. Cabozantinib effectively inhibited angiogenesis, resulting in increased hypoxia in angiogenesis-dependent tumor areas, and induced vessel normalization. Yet, tumors ultimately escaped cabozantinib therapy by diffuse infiltrative outgrowth via vessel co-option. Of importance, in contrast to the results from in vitro experiments, in vivo blockade of c-MET activation was incomplete, possibly due to multiple factors including restoration of the blood-brain barrier resulting from cabozantinib-induced VEGFR2 inhibition. In conclusion, cabozantinib is a promising therapy for c-MET positive glioma, but improving delivery of the drug to the tumor and/or the surrounding tissue may be needed for full activity.

Nuclear phosphorylated Y142 β-catenin accumulates in astrocytomas and glioblastomas and regulates cell invasion

“…These results confirm a key role of c-Met in GBM progression. 29,[48][49][50][51] The lack of regulation of PY142 b-catenin by a c-Met inhibitor does not allow us to conclude if c-Met is phosphorylating this b-catenin site in GBM cells and rather suggests the involvement of other kinases. The proteolytic processing of c-Met is well described and nuclear c-Met has been linked to invasive cancers.…”

The role of the PI3K/AKT/mTOR pathway in brain tumor metastasis

“…[39,40] Inhibitors of c-MET such as cabozantinib are also being considered, and have been reported to induce a significant increase in overall survival of mice bearing GBM xenografts. [41] However, anti-angiogenic therapies targeting VEGF/ VEGFR have had less of an effect than expected. [42] This could be because, in highly vascularized tissues like the lung and brain, tumors can often proliferate around existing vessels and hijack them, a process called vessel cooption.…”

Cabozantinib Is Active against Human Gastrointestinal Stromal Tumor Xenografts Carrying Different KIT Mutations

“…As a multitargeted kinase inhibitor, cabozantinib can act through blocking several RTKs, including KIT, but also other kinases some authors postulate a potential role in GIST as shown in several preclinical models and patient samples (20,32,33). One of cabozantinib's targets is MET, the tyrosine kinase receptor for hepatocyte growth factor which is implicated in the resistance to different TKIs or monoclonal antibodies in several preclinical models and human tumors (34)(35)(36).…”