Frizzled-8 receptor (FZD8) (FZD8)

Frizzled-8 receptor (FZD8) is a member of the Frizzled family of seven-transmembrane domain receptors that serve as the primary receptors for Wnt signaling proteins (UniProt: Q9H461). The cysteine-rich domain (CRD) is the conserved extracellular N-terminal region of Frizzled-8 receptor that is essential for high-affinity binding to Wnt ligands (PubMed: 22843462). In various cancers, including pancreatic, colorectal, and ovarian cancer, Frizzled-8 receptor is often overexpressed, leading to hyperactivation of the Wnt/beta-catenin pathway which promotes tumor growth, stemness, and chemoresistance (PubMed: 25837043). Therapeutic strategies targeting the Frizzled-8 receptor cysteine-rich domain include the development of decoy receptors, such as Ipaficept (OMP-54F28), which consists of the Frizzled-8 receptor cysteine-rich domain fused to a human IgG1 Fc fragment (PubMed: 28137921). This decoy receptor acts by sequestering Wnt ligands, thereby preventing them from activating endogenous receptors and inhibiting downstream signaling (PubMed: 28137921). Additionally, monoclonal antibodies like Vantictumab have been developed to bind the cysteine-rich domain of multiple Frizzled receptors, including Frizzled-8 receptor, to block signaling. However, clinical use of these agents is limited by significant safety concerns, most notably the reduction in bone mineral density due to the inhibition of Wnt signaling in bone homeostasis (PubMed: 28137921). Despite these challenges, Frizzled-8 receptor remains a target of interest for precision medicine in tumors with specific Wnt-pathway mutations.

Other names

Frizzled-8Frizzled class receptor 8FZD8Frizzled-8 cysteine-rich domainFZD8-CRD

Wnt ligand sequestration; Competitive inhibition of Wnt-Frizzled interaction