A Stem Cell-Based Therapy for Colon Cancer

Colorectal cancer is the third leading cause of death in the Western World. Like many other types of cancer, colorectal cancer spreads and is propagated by cancer stem cells. Therefore, understanding how to inhibit the growth of cancer stem cells provides a key to treating the cancer itself.

By inactivating a gene that drives stem cell renewal in cancer stem cells, scientists and surgeons at the Princess Margaret Cancer Centre in Toronto, Canada, have discovered a promising new approach to treating colorectal cancer.

John Dick, a senior scientist at the Princess Margaret Cancer Centre, said, “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.”

In preclinical experiments with laboratory rodents, Dick and his team identified a gene called BMI-1 as a pivotal regulator of colon cancer stem cell proliferation. With this knowledge in hand, Dick’s laboratory dedicated many hours to finding small molecules that disarm BMI-1. Then Dick and his co-workers replicated human colorectal cancer in mice, and used their BMI-1-inhibiting small molecules to treat these cancer-stricken mice.

According to lead author of this work, Antonija Kreso: “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.”

Dr. 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.”

The clinical potential of this approach is significant, since it provides a viable treatment that specifically targets colon cancer. About 65% of all colorectal cancers have an activated BMI-1 pathway. Since physicians now have techniques for identifying the presence of BMI-1 and the tools to inhibit it, this strategy could translate into a clinical treatment that might radically transform the treatment of aggressive, advanced colorectal cancers. Such a treatment would be specific, personal, and specific. May the phase 1 trials begin soon!!!

Reprogramming for Stem Cells

Regenerative medicine possesses tremendous potential. At the center of regenerative medicine is stem cells. How we derive stem cell lines is a central concern of this blog, but I remain convinced that embryonic stem cells do not represent the future of regenerative medicine. My reasons are manifold, but one of my greatest concerns is that embryonic stem cells (ESCs) require the death of human embryos. Human embryos are young human persons at the earliest stages of life. Destroying them is killing an innocent person. There has to be a better way.

Induced pluripotent stem cells (iPSCs) provide one possible alternative to ESCs, and while these cells show tremendous promise, they have their share of problems. While many of the safety concerns with these cells have been nicely addressed, others remain. Is there an even better way?

Hopefully the answer is “yes.” As it turns out, it is possible to reprogram cells to form another cell type without taking them through an embryonic-like stage. This strategy is called reprogramming, and it has been used by Doug Melton and co-workers in his lab at Harvard University to make insulin-making beta cells from other types of pancreas cells that do not normally make insulin (Qiao Zhou, et al., Nature 455, 627-632).  Likewise, the steroid dexamethasone can convert pancreatic cells into liver cells.

Now other researchers have found that small molecules can reprogram cells to become another cell type.  Small molecules can cause unwanted side effects, but James Chen, a chemical biologist at Stanford University School of Medicine, says they “are more in our comfort zone in terms of clinical therapies.”  Chen also said, “Chemists can synthesize and derivatize them, there are standard methods for determining compound pharmacokinetics, and the path to FDA [Food & Drug Administration] approval is well established.”

Researchers also favor small molecules because they have more control over dosage and delivery time with them than they do with genetic techniques.

In 2007, Sheng Ding, chemical biologist at Scripps Research Institute, reported the first small molecule that could substitute for one of the four reprogramming transcription-factor genes. Researchers continue to identify small molecules that can replace one, two, or three of the four reprogramming factors. Among the newest transcription-factor gene stand-ins are molecules such as the lactam kenpaullone from Peter Schultz’s laboratory at Scripps and the heterocyclic RepSox from Lee Rubin and Doug Melton at Harvard Stem Cell Institute (Proc. Nat. Acad. Sci. USA 2009, 106, 8912; Cell Stem Cell 2009, 5, 491).

Reprogramming might be able to do great things.  Out bodies are filled with stem cells.  We just need to know how to manipulate them.