An engineered ligand trap inhibits leukemia inhibitory factor as pancreatic cancer treatment strategy

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Leukemia inhibitory factor (LIF) promotes tumor progression in various cancers, including pancreatic cancer, via KRAS-driven signaling pathways.
• Stromal myofibroblasts and tumor cells are key sources of LIF, contributing to the tumor microenvironment.

Purpose of the Study:

• To engineer a high-affinity soluble human LIF receptor (LIFR) decoy to sequester LIF and inhibit its signaling as a cancer therapeutic strategy.
• To evaluate the efficacy and safety of this engineered LIFR decoy in preclinical models of pancreatic cancer.

Main Methods:

• Engineering of a soluble human LIFR decoy fused to an antibody Fc-domain, resulting in a 'ligand trap'.
• Characterization of the engineered LIFR decoy's binding affinity and LIF inhibitory capacity compared to wild-type LIFR-Fc.
• Assessment of the decoy's ability to block LIF-mediated effects in pancreatic cancer cells in vitro.
• Evaluation of the therapeutic effect on pancreatic cancer xenograft tumor growth in vivo and assessment of potential toxicity in animal models.

Main Results:

• The engineered LIFR decoy demonstrated approximately 50-fold increased affinity for LIF (~20 pM) and superior LIF inhibition compared to wild-type LIFR-Fc.
• The decoy potently inhibited LIF-mediated effects in pancreatic cancer cells.
• Treatment with the LIFR decoy significantly slowed the growth of pancreatic cancer xenograft tumors.
• No apparent toxicity was observed in the animal models, suggesting a favorable safety profile.

Conclusions:

• Engineered LIFR ligand traps are a promising therapeutic strategy for inhibiting LIF signaling in cancer.
• This approach holds potential for the treatment of pancreatic cancer and potentially other LIF-dependent malignancies.
• The observed efficacy and lack of toxicity support further development of ligand trap therapies for cancer treatment.