Drug Conjugates of Antagonistic R-Spondin 4 Mutant for Simultaneous Targeting of Leucine-Rich Repeat-Containing G
Jie Cui1, Yukimatsu Toh1, Soohyun Park1
1Center for Translational Cancer Research, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, 1825 Pressler St., Houston, Texas 77030, United States.
Abstract:
LGR4-6 (leucine-rich repeat-containing G-protein-coupled receptors 4, 5, and 6) are three related receptors with an upregulated expression in gastrointestinal cancers to various extents, and LGR5 is enriched in cancer stem cells. Antibody-drug conjugates (ADCs) targeting LGR5 showed a robust antitumor effect in vivo but could not eradicate tumors due to plasticity of LGR5-positive cancer cells. As LGR5-negative cancer cells often express LGR4 or LGR6 or both, we reasoned that simultaneous targeting of all three LGRs may provide a more effective approach. R-spondins (RSPOs) bind to LGR4-6 with high affinity and potentiate Wnt signaling. We identified an RSPO4 furin domain mutant (Q65R) that retains potent LGR binding but no longer potentiates Wnt signaling. Drug conjugates of a peptibody comprising the RSPO4 mutant and IgG1-Fc showed potent cytotoxic effects on cancer cell lines expressing any LGR in vitro and suppressed tumor growth in vivo without inducing intestinal enlargement or other adverse effects.
Insights
Targeting leucine-rich repeat-containing G-protein-coupled receptors 4-6 (LGR4-6) with novel drug conjugates demonstrated potent anti-tumor effects in gastrointestinal cancers. This approach effectively eradicated tumors by addressing cancer cell plasticity and LGR4/6 expression in LGR5-negative cells.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Leucine-rich repeat-containing G-protein-coupled receptors 4-6 (LGR4-6) are upregulated in gastrointestinal cancers, with LGR5 enriched in cancer stem cells.
- Antibody-drug conjugates (ADCs) targeting LGR5 show antitumor effects but fail to eradicate tumors due to cancer cell plasticity.
- LGR5-negative cells often express LGR4 or LGR6, suggesting a need for broader LGR targeting.
Purpose of the Study:
- To develop a more effective therapeutic strategy for gastrointestinal cancers by simultaneously targeting LGR4, LGR5, and LGR6.
- To investigate the potential of a novel drug conjugate based on an RSPO4 mutant for cancer treatment.
Main Methods:
- Development of a drug conjugate using a peptibody with a mutated RSPO4 (Q65R) and IgG1-Fc.
- In vitro testing of the drug conjugate on cancer cell lines expressing LGR4-6.
- In vivo evaluation of the drug conjugate's efficacy and safety in tumor models.
Main Results:
- The RSPO4 mutant retains high affinity for LGR4-6 but does not potentiate Wnt signaling.
- The drug conjugate exhibited potent cytotoxic effects on cancer cell lines expressing any LGR.
- In vivo studies demonstrated suppressed tumor growth without adverse effects like intestinal enlargement.
Conclusions:
- Simultaneous targeting of LGR4-6 offers a promising therapeutic strategy for gastrointestinal cancers.
- The developed RSPO4-mutant-based drug conjugate is a potent and safe anti-cancer agent, effective against tumors with diverse LGR expression profiles.
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