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Targeting Wnts at the source--new mechanisms, new biomarkers, new drugs
Babita Madan1, David M Virshup2
1Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.
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.
Insights
New Wnt pathway inhibitors targeting Wnt secretion and receptor interactions are in clinical trials. Specific mutations in cancer may predict patient response to these novel upstream Wnt inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Wnt signaling pathway dysregulation is common in various cancers, making it a key therapeutic target.
- Drug development has shifted from targeting downstream effectors like β-catenin to upstream modulators of Wnt secretion and receptor interactions.
- Recent findings highlight the role of cancer-specific Wnt receptor upregulation in modulating cellular sensitivity to Wnt ligands.
Purpose of the Study:
- To review the development of novel upstream Wnt pathway inhibitors for cancer therapy.
- To discuss the significance of Wnt receptor expression and mutations in cancer.
- To explore the potential of specific mutations as predictive biomarkers for novel Wnt-targeted therapies.
Main Methods:
- Review of current literature on Wnt signaling in cancer.
- Analysis of emerging drug development strategies targeting Wnt secretion and Wnt/receptor interactions.
- Examination of genetic alterations (RNF43, ZNRF3, RSPO2, RSPO3) affecting Wnt signaling in cancer.
Main Results:
- Novel therapeutic agents, including Wnt secretion inhibitors and recombinant proteins blocking Wnt-Frizzled interactions, are advancing to clinical trials.
- Cancer-specific upregulation of Wnt receptors influences cellular responsiveness to Wnt signaling.
- Loss-of-function mutations in RNF43/ZNRF3 and gain-of-function translocations in RSPO2/RSPO3 are prevalent and enhance Wnt/β-catenin signaling.
Conclusions:
- Upstream Wnt inhibitors represent a promising new therapeutic avenue for cancer treatment.
- Mutations in RNF43, ZNRF3, RSPO2, and RSPO3 may serve as predictive biomarkers for patient selection in clinical trials of novel Wnt inhibitors.
- Targeting Wnt signaling through upstream modulation offers a refined strategy for cancer therapy.
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