Abstract
Glioblastoma (GBM) is a lethal disease without effective therapies. Previously we reported that the TAM receptor tyrosine kinase family member AXL is upregulated in mesenchymal GBM and its knockdown induces apoptosis of mesenchymal but not proneural glioma sphere cultures (GSCs). In this study, we report that BGB324, a novel small molecule inhibitor for AXL, prolongs the survival of immunocompromised mice bearing mesenchymal GSC-derived GBM-like intracranial tumors by inhibition of AXL activation in tumor cells. Mechanistically, we identified that protein S (PROS1), known as a ligand for other TAM receptors, is secreted by tumor-associated macrophages, thereby physically associates and activates AXL in mesenchymal GSCs. The PROS1-driven phosphorylation of AXL resulted in the NF-kB activation in mesenchymal GSCs and this activation was eliminated by BGB324 treatment. In addition, BGB324 downregulated the immune checkpoint protein PD-L1 both in vitro and in vivo. Combination of BGB324 with Nivolumab - the neutralizing antibody for PD-1 (a receptor for PD-L1) was effective to prolong the survival of immunocompetent mice bearing syngeneic GBM models. Clinically, both AXL and PROS1 expression indicated poorer prognosis of GBM patients. These data suggest that the PROS1/AXL pathway regulates intrinsic mesenchymal signaling as well as extrinsic immune microenvironment, contributing to the growth of aggressive GBM tumors. To translate the pre-clinical data to human GBM patients, we designed a surgical PK/PD clinical trial with BGB324 for recurrent GBM and this trial is currently under review by the Brain Malignancy Steering Committee in the National Cancer Institute.