title: Targeting Wnts at the source--new mechanisms, new biomarkers, new drugs.
abstract: Wnt signaling is dysregulated in many cancers and is therefore an attractive therapeutic target. The focus of drug development has recently shifted away from downstream inhibitors of β-catenin. Active inhibitors of Wnt secretion and Wnt/receptor interactions have been developed that are now entering clinical trials. Such agents include inhibitors of Wnt secretion, as well as recombinant proteins that minimize Wnt-Frizzled interactions. These new therapies arrive together with the recent insight that cancer-specific upregulation of Wnt receptors at the cell surface regulates cellular sensitivity to Wnts. Loss-of-function mutations in RNF43 or ZNRF3 and gain-of-function chromosome translocations involving RSPO2 and RSPO3 are surprisingly common and markedly increase Wnt/β-catenin signaling in response to secreted Wnts. These mutations may be predictive biomarkers to select patients responsive to newly developed upstream Wnt inhibitors.
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.
authors.forename: Babita
authors.initials: B
authors.lastname: Madan
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore. david.virshup@duke-nus.edu.sg.
authors.forename: David M
authors.initials: DM
authors.lastname: Virshup
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002986:Clinical Trials as Topic; D015195:Drug Design; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor