Discovery of small molecule β-catenin suppressors that enhance immunotherapy

Area of Science:

• Pharmacology
• Oncology
• Immunology

Background:

• Targeting β-catenin is crucial for cancer stem cell therapy, but effective suppressors are limited.
• E-cadherin's affinity for β-catenin suggests increasing its expression could regulate β-catenin levels.
• Existing therapies for Wnt/β-catenin pathway dysregulation have significant clinical limitations.

Purpose of the Study:

• To discover and characterize novel small molecules for direct β-catenin downregulation.
• To evaluate the therapeutic potential of Dan-Shen-Su (DSS)-derived compounds in preclinical cancer models.
• To investigate the mechanisms underlying the anti-cancer effects of these novel compounds.

Main Methods:

• Synthesis and screening of ester-based drugs derived from Dan-Shen-Su (DSS).
• Assessment of β-catenin downregulation and E-cadherin expression modulation.
• Evaluation of therapeutic efficacy in post-surgery mice, including survival rates.
• Combination therapy studies with PD-L1 checkpoint blockade.
• Mechanistic studies, including vitamin D receptor agonism assessment.

Main Results:

• Discovery of DSS-C12 and DSS-B8, potent β-catenin downregulators.
• Demonstrated improvement in overall survival in mice treated with DSS compounds.
• Enhanced systemic immune responses and significant primary tumor growth suppression when combined with PD-L1 blockade.
• DSS-B8 identified as a vitamin D receptor agonist without causing hypercalcemia.

Conclusions:

• DSS-derived small molecules offer a promising therapeutic strategy for direct β-catenin deactivation.
• These compounds have potential for clinical application in cancer treatment, particularly in combination therapies.
• The findings highlight a novel approach to targeting cancer stem cells and enhancing anti-tumor immunity.