A promising new approach to treating colorectal cancer involves disarming the gene that drives self-renewal in the stem cells that are the root cause of disease, treatment resistance, and relapse. Colorectal cancer is the third leading cause of cancer-related death in the Western world.
“This is the first step toward clinically applying the principles of cancer stem cell biology to control cancer growth and advance the development of durable cures,” said principal investigator John Dick, PhD, of Princess Margaret Hospital in Toronto, Canada. The findings were published in Nature Medicine (2013; doi:10.1038/nm.3418).
Dick pioneered the cancer stem cell field by first identifying leukemia stem cells (in 1994) and colon cancer stem cells (in 2007). He is also renowned for isolating a human blood stem cell in its purest form —as a single stem cell capable of regenerating the entire blood system—paving the way for clinical use (in 2011).
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In preclinical experiments, the research team replicated human colon cancer in mice to determine if specifically targeting the stem cells was clinically relevant. First, the researchers determined that the gene BMI-1, already implicated in maintaining stem cells in other cancers, is the pivotal regulator of colon cancer stem cells and drives the cycle of self-renewal, proliferation, and cell survival. Next, the team used an existing small-molecule inhibitor to successfully block BMI-1, thus demonstrating the clinical relevance of this approach.
“Inhibiting a recognized regulator of self-renewal is an effective approach to control tumor growth, providing strong evidence for the clinical relevance of self-renewal as a biological process for therapeutic targeting,” wrote lead author Antonija Kreso, PhD.
Dick explained, “When we blocked the BMI-1 pathway, the stem cells were unable to self-renew, which resulted in long-term and irreversible impairment of tumor growth. In other words, the cancer was permanently shut down.”
Surgeon-scientist Catherine O’Brien, MD, PhD, of Princess Margaret Hospital and senior coauthor of the study expressed excitement about the clinical potential of this research. She explained that it maps a viable way to develop targeted treatment for colon cancer. About 65% of colon cancers have the BMI-1 biomarker. She explained that this knowledge could readily translate into first-in-human trials since the target is identified and a proven way to tackle it exists.
