R-spondins (RSPOs) are secreted proteins with critical roles in cancer development through binding to LGRs and RNF43/ZNRF3 and potentiating Wnt signaling. Various RSPO mutants were discovered that bind to LGRs but no longer function in Wnt signaling. Fc fusion protein of the RSPO mutants, so-called RSPO peptides, were conjugated with cytotoxic drugs, and the resulting conjugates were able to inhibit the growth of cancer cells expressing LGR4, LGR5, and/or LGR6 in vitro and in vivo without major adverse effect.
RSPOs and LGR4-6 (leucine-rich repeat-containing, G protein-coupled receptors 4, 5, and 6) form a ligand-receptor system that strongly potentiates Wnt signaling through inhibition of two E3 ligases RNF43/ZNRF3. Genetic mutations of RSPOs occur in a subset of human cancers as a driving factor and over-expression of LGR4-6 was found in the majority of gastrointestinal cancers. Specific targeting of RSPO-LGR for cancer treatment has been pursued by various approaches, including antibodies and antibody-drug conjugates.
Researchers at UTHealth have engineered mutants of RSPOS that can bind to all three LGRs with high affinity but no longer function in Wnt signaling. The mutants even function as antagonists of active RSPOs. Fc-fusion proteins of these mutants, called antibodies, have substantially longer half-life in vivo. Drug conjugates of the RSPO peptides (PDCs) were found to inhibit the growth of cancer cells expressing any of the three LGRs in vitro and in vivo without major adverse effects.
The plasticity of cancer cells is often associated with drug resistance and LGR5-positive cells may switch between LGR4 and LGR5/6 expression. The PDCs generated here effectively bind all three LGR receptor types with high affinity, and therefore may overcome plasticity and drug resistance.
The antibodies as well as the PDCs are potential drug candidates that may provide diagnosis and treatment for a wide range of cancers, since LGRs are expressed broadly and highly in solid tumors, particularly in cancers of the digestive system, such as colon, stomach, and liver cancer.
- The peptides can specifically block RSPO-LGR signaling and thus inhibit cancer cell growth.
- The peptides can be used to detect cancer in a patient through the detection of increased LGR levels.
- The PDCs can be developed as cancer therapeutics.
Intellectual Property Status
- U.S. Utility Patent Application Filed
- Available for licensing
Stage of Development
“Drug Conjugates of Antagonistic R-Spondin 4 Mutant for Simultaneous Targeting of Leucine-Rich repeat-containing G Protein-Coupled Receptors 4/5/6 for Cancer Treatment.”
About the Lead Creator/Inventor
Professor and Director, Center for Translational Cancer Research, Brown Foundation Institute of Molecular Medicine;
Leads a research team primarily focused on the identification and characterization of targeted drug candidates in the area of cancer and immunology.
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