Foretinib Is Effective Therapy for Metastatic Sonic Hedgehog Medulloblastoma

Abstract

Medulloblastoma is the most common malignant pediatric brain tumor, with metastases present at diagnosis conferring a poor prognosis. Mechanisms of dissemination are poorly understood and metastatic lesions are genetically divergent from the matched primary tumor. Effective and less toxic therapies that target both compartments have yet to be identified. Here, we report that the analysis of several large nonoverlapping cohorts of patients with medulloblastoma reveals MET kinase as a marker of sonic hedgehog (SHH)-driven medulloblastoma. Immunohistochemical analysis of phosphorylated, active MET kinase in an independent patient cohort confirmed its correlation with increased tumor relapse and poor survival, suggesting that patients with SHH medulloblastoma may benefit from MET-targeted therapy. In support of this hypothesis, we found that the approved MET inhibitor foretinib could suppress MET activation, decrease tumor cell proliferation, and induce apoptosis in SHH medulloblastomas in vitro and in vivo. Foretinib penetrated the blood-brain barrier and was effective in both the primary and metastatic tumor compartments. In established mouse xenograft or transgenic models of metastatic SHH medulloblastoma, foretinib administration reduced the growth of the primary tumor, decreased the incidence of metastases, and increased host survival. Taken together, our results provide a strong rationale to clinically evaluate foretinib as an effective therapy for patients with SHHdriven medulloblastoma. Cancer Res; 75(1); 134-46. Ó2014 AACR.

Foretinib Overcomes Entrectinib Resistance Associated with the NTRK1 G667C Mutation in NTRK1 Fusion–Positive Tumor Cells in a Brain Metastasis Model

“…In a preclinical study, foretinib was reported to be able to penetrate the BBB (the penetration of the drug in the brain was 14%) and reduce the growth of medulloblastoma cells in an orthotopic CNS dissemination model (35). In line with these results, we demonstrated that foretinib inhibits the tumor progression due to KM12SM-ER cells in a brain metastasismimicking model.…”

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

“…[104] This inhibition blocked the EMT induced by VEGF ablation in a GBM mouse model [105] and induced an effective decrease in MB cell migration and invasion. [106,107] Stromal cell derived factor (SDF-1) or CXCL2 and its chemokine receptor CXCR4 can induce EMT in GBM via activation of PI3K/AKT and extracellular-signal-regulated kinases (ERK) pathways, and its inhibition suppressed EMT in glioma cell lines by upregulating E-cadherin. [108] However, single agents targeting the PAM pathway have been reported to be an inefficient approach in MB and to increase invasion in the surviving fraction of GBM.…”

Brain tumor modeling using the CRISPR/Cas9 system: state of the art and view to the future

“…For example, it was reported that the rat glioma model could be induced by implantation of cultured glioma cells (Cell-derived xenograft: CDX) [3, 4] and transplanted tumor fragments (Patient-derived xenograft: PDX) [5]. Medulloblastom was regarded as the most common malignant brain tumor in pediatrics with a poor prognosis and in vivo investigation; it was often induced by transplantation of chemically modified human medulloblastoma cells such as Daoy, ONS76 and D425 [6]. Although these animal models have the advantage of making the tumor models for a short time and are widely used for the study of brain tumors, they do not comprehensively recapitulate human neoplasms and often caused the inhibitory tumor-host immunoresponses [7, 8].…”