Colon Cancer Target Found By Stem Cell Pioneer - Drug Discovery and Development

The researcher who discovered the first blood cancer stem cell in the 1990s has now identified a small molecule that can target a critical colon cancer stem cell gene.

John Dick, director of the Program in Cancer Stem Cells, Ontario Institute for Cancer Research (OIC), reported in Nature Medicine recently that a small molecule inhibitor, PTC-209, successfully targets the gene Bmi-1, and irreversibly halts production of colon cancer stem cells.

“This project had no surprises, but it did offer satisfaction that the hypothesis that Bmi-1 functions to regulate cancer stem cells seems to bear out,” Dick tells Drug Discovery & Development. “We had done all the genetic studies some time ago and knew it would be a nice confirmatory story based on the regulation of Bmi-1 in other stem cell systems. The good fortune was that (lead-author and OIC researcher) Catherine O’Brien met Tom Davis (of PTC Therapeutics) at a cancer meeting and realized that they had a small molecule. From then we were able to show that the drug worked as expected. This broadened our findings because it offered a picture of future clinically relevant targeting of such a hallmark biological property of stem cells-self renewal. The paper points to self-renewal as a tractable biological process to target clinically.”

Colon cancer is the second greatest cause of cancer-related deaths. After conventional treatment, half of all colon cancers come roaring back. The reason for this, Dick’s group has suggested, is that virulent colon cancer stem cells at the heart of the cancers can lie dormant, resistant to traditional chemotherapies that rely on cell replication to work—then spring to life later, post-chemo. In this, they are mimicking the behavior of normal stem cells, which can both self-renew and lay dormant for long periods of time.

The team of Michael Clarke of the University of Michigan first discovered in 2003 that Bmi-1 was a critical driver of blood stem cells. In 2007, Dick’s group was among the first to characterize colon cancer stem cells.

In the new paper, Dick’s group first proved that Bmi-1 is not just important to colon cancer stem cells, but is their pivotal driver. Then the group tried PTC-209 on cells expressing Bmi-1 (about 65% of colon cancer cells). It blocked the Bmi-1 pathway so well the stem cells ceased replicating, and tumor growth was irreversibly halted.

“Collectively, our data indicate that colorectal cancer cells are highly dependent on Bmi-1, which functions as a pleiotropic regulator that maintains the viability and proliferative capacity of colorectal cancer cells in general but also governs (cancer stem cell) self-renewal,” the group wrote. “PTC-209 reduced tumor volume and reduced the number of functional colorectal CICs, even following short-term treatment, a result that contrasts with the enrichment of CICs observed following conventional chemotherapy.”

One problem with cancer stem cells is that many genes marking them are also expressed on normal stem cells. So therapies targeting them can end up harming healthy stem cells, too. But the group found that, while earlier studies reported diphtheria toxin kills colon cancer stem cells and healthy stem cells both, this did not seem to occur with PTC-209. “With PTC-209, no changes in digestive function in the treated mice were identified, indicating that the dose we used to lower tumor burden does not noticeably affect the intestinal system,” the group wrote.

Dick is credited with isolating the first blood cancer stem cells in 1994. He also wrote many of the pioneering papers on the isolation of the first healthy blood stem cells.

His group is looking at PTC-209 and other small molecule inhibitors for colon cancer.