Introduction: Medulloblastoma is the most common malignant brain tumor of children. Poor prognosis is associated with an invasive phenotype, characterized by proliferation and the ability to invade surrounding tissue. Our laboratory and colleagues have identified that activity of the protease cathepsin B is strongly associated with the invasive phenotype. We hypothesized that inhibition of cathepsin B would result in a reduction of these tumor-related activities. In this study, we investigated the therapeutic potential of a cathepsin B inhibitor, CA074ME, in medulloblastoma.

Methods: Established human medulloblastoma cell lines were grown and baseline proliferation and invasion characteristics were quantitated using the Cell Counting Kit-8 (CCK8) assay for proliferation and the trans-well invasion assay was used for invasion. Cell lines were then treated with increasing concentrations of CA074ME, with changes in proliferation and invasion measured then subjected to standard statistical analysis.

Results: Inhibition of cathepsin B with CA074ME produced a dose-dependent reduction, up to 4-fold in magnitude, of proliferation of medulloblastoma cell lines (with the exception of extremely low doses, which had a paradoxical effect on proliferation). Similarly, invasion was significantly reduced by ~75% in a dose-dependent manner.

Conclusions: Inhibition of cathepsin B markedly influences medulloblastoma phenotype, reducing both proliferation and invasion in a dose-dependent manner. These data suggest a novel method to pharmacologically target clinically significant tumor activity.

Patient Care: This research offers insight to possible new brain tumor treatments.

Learning Objectives: By the conclusion of this session, participants should be able to (1) discuss the importance of the invasive phenotype in medulloblastoma, (2) describe the influence of proteases on the invasive phenotype of medulloblastoma and (3) identify the potential utility of pharmacologic blockade of cathepsin B in this tumor type

References: Netrin-1 promotes glioblastoma cell invasiveness and angiogenesis by multiple pathways including activation of RhoA, cathepsin B, and cAMP-response element-binding protein. Shimizu A, Nakayama H, Wang P, König C, Akino T, Sandlund J, Coma S, Italiano JE Jr, Mammoto A, Bielenberg DR, Klagsbrun M. Urinary biomarkers predict brain tumor presence and response to therapy. Smith ER, Zurakowski D, Saad A, Scott RM, Moses MA. Clin Cancer Res. 2008 Apr 15;14(8):2378-86.