Colorectal cancer is the third leading cause of cancer-related death in the Western world. And although it is a highly treatable and often curable disease when localized to the bowel, surgery is still the primary form of treatment which results in a cure in approximately 50% of the patients. Recurrence following surgery is a major problem and is often the ultimate cause of death.
Based on recent estimates from the American Cancer Society, there will be 102,480 new cases and 50,830 in 2013. Historically, black people have had the highest rate of getting colorectal cancer, followed by white, Hispanic, Asian/Pacific Islander, and American Indian/Alaska Native people.
A new approach
Now, for the first time, scientists and surgeons at Princess Margaret Cancer Centre, a teaching hospital in Toronto, Ontario, Canada, affiliated with the University of Toronto Faculty of Medicine as part of the University Health Network, have discovered a promising new approach to treating colorectal cancer.
Blocking the BMI-1 pathway results in stem cells unable to self-renew, which, in turn, resulted in long-term and irreversible impairment of tumor growth.
Based on available evidence, cancer-initiating cells or CIC gene signatures influence patient survival. Various studies suggest that targeting self-renewal, the key stemness property unique to CICs, may represent a new paradigm in cancer therapy. Hence, as part of their new approach, the researchers disarmed the gene that drives self-renewal in stem cells that are the root cause of disease, resistance to treatment and relapse.
“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,” noted principal investigator John E. Dick. Ph.D, a pioneer in the cancer stem cell research who first identified leukemia stem cells (1994) and colon cancer stem cells (2007). The the findings of his study are published in the December 1, 2013 online edition ofNature Medicine.
Cycle of self-renewal
In pre-clinical experiments, the research team replicated human colon cancer in mice to determine if specifically targeting the stem cells was clinically relevant. First, the researchers identified 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,” noted lead author Antonija Kreso, Ph.D, a scientist working under Dick’s direction in his laboratory at Princess Margaret Cancer Centre, University Health Network.
“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.” Dick further explained
Surgeon-scientist Catherine O’Brien, another scientist working with Dick and senior co-author of the study explained: “The clinical potential of this research is exciting because it maps a viable way to develop targeted treatment for colon cancer patients. It is already known that about 65% have the BMI-1 biomarker. With the target identified, and a proven way to tackle it, this knowledge could readily translate into first-in-human trials to provide more personalized cancer.”
Video: Princess Margaret scientists and surgeons have discovered a new approach to treating colorectal cancer – by disarming the gene that drives self-renewal in stem cells that are the root cause of disease, resistance to treatment and relapse.
Photo: John Dick, Ph.D, Senior Scientist, Princess Margaret Cancer Centre, and a team of researchers at the Princess Margaret have discovered a new approach to treating colorectal cancer. Photo Courtesy: UHN
For more information:
Kreso A, Van Galen P, Pedley NM, Lima-Fernandes E, Frelin C, Davis T, Cao L, et al. Self-renewal as a therapeutic target in human colorectal cancer. Nature Medicine 2013, Dec. 1 doi:10.1038/nm.3418 [Article] [Supplementary Files]
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