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Targeting Wnts at the Source—New Mechanisms, New Biomarkers, New Drugs Babita Madan and David M

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Targeting Wnts at the Source—New Mechanisms, New Biomarkers, New Drugs Babita Madan and David M Published OnlineFirst April 21, 2015; DOI: 10.1158/1535-7163.MCT-14-1038 Review Molecular Cancer Therapeutics Targeting Wnts at the Source—New Mechanisms, New Biomarkers, New Drugs Babita Madan and David M. Virshup Abstract Wnt signaling is dysregulated in many cancers and is therefore cific upregulation of Wnt receptors at the cell surface regulates an attractive therapeutic target. The focus of drug development has cellular sensitivity to Wnts. Loss-of-function mutations in RNF43 recently shifted away from downstream inhibitors of b-catenin. or ZNRF3 and gain-of-function chromosome translocations Active inhibitors of Wnt secretion and Wnt/receptor interactions involving RSPO2 and RSPO3 are surprisingly common and have been developed that are now entering clinical trials. Such markedly increase Wnt/b-catenin signaling in response to secreted agents include inhibitors of Wnt secretion, as well as recombinant Wnts. These mutations may be predictive biomarkers to select proteins that minimize Wnt–Frizzled interactions. These new patients responsive to newly developed upstream Wnt inhibitors. therapies arrive together with the recent insight that cancer-spe- Mol Cancer Ther; 14(5); 1–8. Ó2015 AACR. Introduction standing the mechanism underlying increased Wnt signaling can guide the therapeutic approach. Wnts are secreted proteins that are critical for normal embry- onic development and homeostasis of select adult tissues. Wnt b signaling regulates diverse developmental and homeostatic func- Downstream Wnt/ -Catenin Pathway tions, including proliferation, differentiation, cell polarity, motil- Inhibitors ity, and migration. In humans, there are 19 WNT ligands that Many downstream components of the Wnt/b-catenin pathway couple to multiple receptors and coreceptors to activate various can be mutated in cancers to stabilize b-catenin protein. Well- downstream pathways. The most extensively studied Wnt signal- recognized activating mutations include truncating mutations of ing pathway follows from the binding of Wnts to a Frizzled (FZD) APC, found in the majority of colorectal cancers, stabilizing and a Lipoprotein receptor-related protein coreceptor, LRP5 or mutations of CTNNB1 (b-catenin) in diverse tumors, and loss- LRP6. A well-studied series of intracellular events cause inhibition of-function mutations of AXIN1/2 in biliary tract and liver cancers of GSK3 and the stabilization of b-catenin (1, 2). This leads to (6). The correlation of b-catenin stabilization with cancer has led cytoplasmic accumulation and then translocation of b-catenin to to the conclusion that stabilized b-catenin can cause cancer, the nucleus where it interacts with members of the TCF/LEF family although in most cases, this has not been rigorously demonstrated of transcription factors to regulate the cell-type specific expression (8). Multiple attempts to target elevated downstream Wnt sig- of target genes (1). Wnts also have important functions indepen- naling have used small molecules that inhibit b-catenin abun- dent of b-catenin, for example, by triggering downstream path- dance or its transcriptional activating activity (Fig. 1; refs. 9–12). ways that regulate tissue polarity and cell movement through the Screens for downstream inhibitors have provided an important activation of RhoA, JNK, and nemo-like kinase signaling cascades insight that b-catenin stability can be regulated by tankyrase- (3–5). mediated degradation of AXIN (11, 13). Tankyrase inhibitors Dysregulated Wnt signaling is associated with various patho- increase AXIN abundance and therefore increase b-catenin deg- logic states, including osteoporosis, cancer, vascular diseases, and radation. Such drugs have been independently developed by fibrosis (6). Elevated Wnt signaling promotes tumorigenesis by several groups, although their oral use may be limited by mech- supporting cellular proliferation, blocking differentiation, driving anism-based gut toxicity (14). A more selective approach is use of epithelial mesenchymal transitions, and promoting both stem small molecules to modulate b-catenin's interaction with tran- cell renewal and metastasis (5, 7). Pathologic Wnt signaling can be scriptional coactivators such as CREB-binding protein (CREBBP/ driven by upstream or downstream events. Targeting the Wnt CBP). One such small molecule, PRI-724, is in phase I trials for signaling pathway can be beneficial for diseases with elevated or acute myeloid leukemia (clinicaltrials.gov NCT01606579) and diminished Wnt activity. Recent findings demonstrate that under- advanced solid tumors (clinicaltrials.gov NCT01302405; ref. 15). Inhibitors directed at b-catenin accumulation will, however, not block signaling pathways triggered by b-catenin–independent Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Med- actions of Wnts. ical School, Singapore. Corresponding Author: David M. Virshup, Duke-NUS Graduate Medical School, 07-20, 8 College Road, Singapore 169857. Phone: 65-6516-7881; Fax: 65-6221- Upstream Inhibitors of Wnt Production and 2402; E-mail: [email protected] Function doi: 10.1158/1535-7163.MCT-14-1038 To inhibit both b-catenin–dependent and –independent sig- Ó2015 American Association for Cancer Research. naling, studies have focused on upstream elements of Wnt www.aacrjournals.org OF1 Downloaded from mct.aacrjournals.org on September 30, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst April 21, 2015; DOI: 10.1158/1535-7163.MCT-14-1038 Madan and Virshup Figure 1. Inhibitors of canonical Wnt/ b-catenin signaling. The binding of Wnts to their receptors, Frizzleds, and coreceptors, LRP5/6, initiates a cascade of signaling events mediated by phosphorylation of Dishevelled and LRP6. The recruitment of the scaffolding protein AXIN1 to the receptor complex leads to inhibition of GSK3 and the b-catenin destruction complex. This is followed by the translocation of b-catenin to the nucleus where its association with TCF family members and coactivators, including CBP and p300, activates transcription of multiple Wnt/b-catenin target genes. Numerous inhibitors that target various nodes of the Wnt/ b-catenin pathway are indicated. signaling, including Wnt production and Wnt ligand–receptor clinical trials (21, 22). It is likely that Ipafricept may interact interactions. Wnts secreted from sending cells interact with Friz- with a subset of the 19 Wnt ligands. Finally, Wnt signaling is zleds, LRP5/6 coreceptors, and various other receptors on the markedly stimulated by R-Spondins (RSPO) both physiologi- surface of receiving cells. Figure 2A illustrates our current under- cally, and pathologically when they are overexpressed due to standing of Wnt secretion. Figure 2B illustrates the regulation of specific chromosomal translocations (23, 24). Neutralizing cell surface Wnt receptors and the targets of upstream Wnt antibodies against RSPOs are also being developed (ref. 25; inhibitors (recently reviewed in ref. 4). and others). These recombinant proteins and monoclonal One disorder where it is clinically valuable to increase Wnt antibodies have high specificity, low off-target effects, and signaling is osteoporosis. Sclerostin (SOST) is an osteocyte-spe- infrequent dosing, but share issues of parenteral administra- cific Wnt inhibitor that interacts with LRP4 as well as LRP5/6 to tion, long half-lives, and slow off-rates. inhibit excessive bone formation (Fig. 2). SOST and LRP4 loss-of- An alternative approach to blocking Wnt signaling upstream function mutations cause increased bone mass, a finding that can is the use of orally available small molecules that prevent Wnt be mimicked therapeutically for the treatment of osteoporosis by ligand biogenesis and secretion. All mammalian Wnts require SOST or LRP4 neutralizing antibodies (16, 17). posttranslational acylation. A single essential, nonredundant Monoclonal antibodies and decoy receptors can also block enzyme, PORCN (the human ortholog of the Drosophila gene the interaction of Wnts with its receptors. Although early porcupine) adds a mono-unsaturated palmitoleate moiety to a studies examined antibodies directed against Wnts, recent work serine residue conserved in all mammalian Wnts (26–28). This has focused on inhibition of Wnt receptors. Examples include palmitoleation is essential for both Wnt secretion, and the anti-LRP6 antibodies (18), and the anti-Frizzled antibody van- binding of Wnts to their receptors (Fig. 2A; refs. 13, 29–31). tictumab (OMP-18R5; ref. 19). Vantictumab binds to 5 of the Thus, inhibition of PORCN blocks the secretion and activity of 10 Fzd receptors recognizing an epitope spanning the "cleft" all human Wnts (32, 33). Small-molecule PORCN inhibitors region of Fzd that contains highly conserved residues (19, 20). circumvent some of the limitations of the recombinant pro- Vantictumab may effectively target a subset of cancers that are tein/monoclonal antibody approaches, and will inhibit both dependent on the function of the appropriate Fzds. A related canonical and noncanonical signaling pathways. Several approach uses a soluble Fzd-based decoy receptor related to the PORCN inhibitors are being developed and have been shown soluble Frizzled-related proteins (sFRP; Fig. 2) that prevents the to be effective in cell- and mouse-based models of Wnt-depen- interaction of Wnts with their primary receptors. One such dent cancers (refs. 30, 34, 35; Madan and colleagues; unpub- recombinant protein, Ipafricept (OMP-54F28), has reached lished results). For all of the upstream Wnt inhibitors, one
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