Identification and Characterization of a Small-Molecule Inhibitor of Wnt Signaling in Glioblastoma Cells

Abstract

Glioblastoma multiforme (GBM) is the most common and prognostically unfavorable form of brain tumor. The aggressive and highly invasive phenotype of these tumors makes them among the most anatomically damaging human cancers with a median survival of less than one year. Although canonical WNT pathway activation in cancers has been historically linked to the presence of mutations involving key components of the pathway (APC, β-CATENIN or AXIN proteins), an increasing number of studies suggest that elevated WNT signaling in GBM is initiated by several alternative mechanisms that are involved in different steps of the disease. Therefore, inhibition of WNT signaling may represent a therapeutically relevant approach for GBM treatment. After the selection of a GBM cell model responsive to WNT inhibition, we set out to develop a screening approach for the identification of compounds capable of modulating canonical WNT signaling and associated proliferative responses in GBM cells. Here we show that the small molecule SEN461 inhibits the canonical WNT signaling pathway in GBM cells, with relevant effects at both molecular and phenotypic levels in vitro and in vivo. These include SEN461-induced AXIN stabilization, increased β-CATENIN phosphorylation/degradation, and inhibition of anchorage-independent growth of human GBM cell lines and patient-derived primary tumor cells in vitro. Moreover, in vivo administration of SEN461 antagonized WNT signaling in Xenopus embryos and reduced tumor growth in a GBM xenograft model. These data represent the first demonstration that small molecule-mediated inhibition of WNT signaling may be a potential approach for GBM therapeutics.

WNT signaling in glioblastoma and therapeutic opportunities

“…158 Recent chemical screening efforts have identified several small-molecule inhibitors and antibodies targeted at WNT signaling (Table 3). 159 A random selection of 16 000 small molecules were used in the screening. SEN461 was selected as a potent WNT signaling inhibitor and validated the molecular mechanism of action.…”

Pharmacologic Wnt Inhibition Reduces Proliferation, Survival, and Clonogenicity of Glioblastoma Cells

“…One recent study tested the AXIN stabilizer SEN461, which showed promising therapeutic effects and inhibited WNT activity in GBM cells in vitro and in vivo (86). Lan et al used aspirin to suppress both WNT signaling and the invasion and survival of GBM cells, although this the anti-inflammatory agent can have a variety of effects (87).…”

Mechanisms regulating glioma invasion

“…For instance, SEN461 (Siena), a small-molecule inhibitor of the Wnt pathway, has been shown to inhibit canonical Wnt signaling by stabilizing Axin and increasing β-catenin degradation in vitro and in vivo. This inhibitor’s effect on GBM invasion has not been tested yet but it has been reported to reduce growth of GBM xenograft models [41]. Therefore, SEN461 may be useful for potential therapy of GBM, although no clinical trials have begun to test it [42].…”