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Updated: Oct 10, 2025
Discovery of Driver Genes in Colorectal HT29-derived Cancer Stem-Like Tumorspheres
Published on: July 22, 2020
Pharmacological targeting of Sam68 functions in colorectal cancer stem cells
Angelique N Masibag1, Christopher J Bergin1, Joshua R Haebe1
1Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
Abstract:
Cancer stem cells (CSCs) are documented to play a key role in tumorigenesis and therapy resistance. Despite significant progress in clinical oncology, CSC reservoirs remain elusive and difficult to eliminate. Reverse-turn peptidomimetics were characterized as disruptors of CBP/beta-Catenin interactions and represent a promising avenue to curb hyperactive canonical Wnt/beta-Catenin signaling in CSCs. Recent studies suggested Sam68 as a critical mediator of reverse-turn peptidomimetics response in CSC populations. Using computational and biochemical approaches we confirmed Sam68 as a primary target of reverse-turn peptidomimetics. Furthermore, we executed an in silico drug discovery pipeline to identify yet uncharacterized reverse-turn peptidomimetic structures displaying superior anti-CSC activity in transformed pluripotent and colorectal cancer cell models. Thus, we identified YB-0158 as a reverse-turn peptidomimetic small molecule with enhanced translational potential, altering key hallmarks of human colorectal CSCs in patient-derived ex vivo organoids and in vivo serial tumor transplantation.
Insights
New reverse-turn peptidomimetics target Sam68 to disrupt cancer stem cell (CSC) signaling. YB-0158 shows promise in eliminating CSCs, offering a potential new therapy for colorectal cancer.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Cancer stem cells (CSCs) drive tumor growth and treatment resistance.
- Hyperactive Wnt/beta-Catenin signaling is crucial for CSCs.
- Reverse-turn peptidomimetics disrupt CBP/beta-Catenin interactions.
Purpose of the Study:
- To identify novel reverse-turn peptidomimetics targeting CSCs.
- To investigate Sam68 as a mediator of peptidomimetic response in CSCs.
- To develop small molecules with enhanced anti-CSC activity.
Main Methods:
- Computational drug discovery pipeline.
- Biochemical validation of Sam68 as a target.
- In silico screening of peptidomimetic structures.
- Ex vivo organoid and in vivo transplantation models.
Main Results:
- Sam68 confirmed as a primary target of reverse-turn peptidomimetics.
- Identified YB-0158, a novel peptidomimetic small molecule.
- YB-0158 demonstrated superior anti-CSC activity in preclinical models.
- YB-0158 altered key hallmarks of human colorectal CSCs.
Conclusions:
- Sam68 is a critical mediator for reverse-turn peptidomimetics in CSCs.
- YB-0158 represents a promising therapeutic candidate for colorectal CSCs.
- Targeting CSCs via Wnt/beta-Catenin pathway offers a viable strategy.
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