The Soluble Wnt Receptor Frizzled8CRD-hFc Inhibits the Growth of Teratocarcinomas In vivo

Abstract

Wnt signaling is important for normal cell proliferation and differentiation, and mutations in pathway components are associated with human cancers. Recent studies suggest that altered wnt ligand/receptor interactions might also contribute to human tumorigenesis. Therefore, agents that antagonize wnt signaling at the extracellular level would be attractive therapeutics for these cancers. We have generated a soluble wnt receptor comprising the Frizzled8 cysteine-rich domain (CRD) fused to the human Fc domain (F8CRDhFc) that exhibits favorable pharmacologic properties in vivo. Potent antitumor efficacy was shown using the mouse mammary tumor virus-Wnt1 tumor model under dosing conditions that did not produce detectable toxicity in regenerating tissue compartments.

Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors

“…OMP-18R5 did not display activity in colon tumors harboring APC or β-catenin mutations, but was highly active in a colon tumor with wildtype APC and β-catenin. OMP-18R5 also inhibited the growth of the established cell line PA-1 (derived from a human teratocarcinoma), which had previously shown to be inhibited by FZD8-fc protein (12) (Fig. 3F).…”

“…This selectivity relative to potential intracellular signaling components may offer advantages in safety and therapeutic index. Previous studies have indicated that use of soluble Wnt inhibitors and decoy receptor molecules can impact tumor growth (11,12). In this article we demonstrate the ability to generate a potent Wnt inhibitory antibody that functions by binding to select Fzd receptors, and that this antibody is active across a range of human tumor types.…”

“…S2). Interestingly, each of these receptors has been previously implicated in canonical Wnt signaling (12)(13)(14)(15)(16)(17). The epitope on the Fzd proteins bound by OMP-18R5 was mapped through a survey of introduced amino acid substitutions within FZD8, several of which eliminated OMP-18R5 binding ( Fig.…”

Canonical Wnt signaling inhibits osteoclastogenesis independent of osteoprotegerin

“…Because the induction of Fzd8 expression during osteoclastogenesis occurs before the (CRD; Fig. 5 E), which can be used to block receptor binding (DeAlmeida et al, 2007;Schulte and Bryja, 2007).…”

Blocking Wnt signaling by SFRP-like molecules inhibits in vivo cell proliferation and tumor growth in cells carrying active β-catenin

“…Thus, SFRPs can modulate Wnt signaling by sequestering Wnts through the CRD or by acting as dominantnegative inhibitors, forming inactive complexes with the frizzled receptors (Bovolenta et al, 2008). In addition, engineered SFRP-like proteins such as the soluble CRD of the receptor Frizzled 8 potently inhibit autocrine Wnt signaling and tumor growth in mice carrying teratomas (DeAlmeida et al, 2007).…”