The Wnt Pathway Inhibitor RXC004 Blocks Tumor Growth and Reverses Immune Evasion in Wnt Ligand-dependent Cancer...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Wnt signaling pathway dysregulation is a key driver in gastrointestinal cancers.
• Targeting the Wnt pathway is challenging due to toxicity and lack of druggable targets.
• No approved therapies currently exist to directly target the Wnt pathway in these cancers.

Purpose of the Study:

• To discover and characterize RXC004, a potent and selective inhibitor of Porcupine, an enzyme essential for Wnt ligand secretion.
• To evaluate the efficacy of RXC004 in preclinical models of colorectal and pancreatic cancers.
• To assess the impact of RXC004 on tumor metabolism and immune evasion.

Main Methods:

• In vitro and in vivo studies of RXC004's pharmacokinetic profile and safety.
• Assessment of RXC004's effects on Wnt ligand palmitoylation, secretion, and pathway activation.
• Evaluation of RXC004's anti-proliferative effects in genetically defined cancer cell lines and xenograft models.
• Analysis of RXC004's impact on tumor cell metabolism using glucose uptake and PET imaging.
• Investigation of RXC004's effects on tumor immunity in syngeneic mouse models and human cell cocultures.

Main Results:

• RXC004 demonstrated a favorable pharmacokinetic profile and effectively inhibited Wnt signaling.
• The drug showed potent anti-proliferative effects in Wnt ligand-dependent colorectal and pancreatic cancer models.
• RXC004 reduced tumor growth and increased cancer cell differentiation in xenograft models, with a therapeutic window.
• Tumor metabolism was modulated by RXC004, as evidenced by changes in glucose uptake and PET imaging.
• RXC004 stimulated anti-tumor immunity by reducing myeloid-derived suppressor cells and synergizing with anti-PD-1 therapy.

Conclusions:

• RXC004 is a potent Porcupine inhibitor with significant anti-cancer activity in Wnt-dependent gastrointestinal cancers.
• The compound exhibits multiple anti-cancer mechanisms, including direct tumor cell killing, metabolic modulation, and immune system stimulation.
• RXC004 has a promising therapeutic window and has advanced to Phase II clinical trials for Wnt-driven gastrointestinal cancers.