A team of Hamilton scientists at the Stem Cell and Cancer Research Institute (SCC-RI) of McMaster University have made a breakthrough discovery (reported by CTV here) with the potential to significantly impact future cancer treatment, and provide new hope for people living with cancer including tens of thousands of Canadians. Published in last Thursday’s edition of CELL, the researchers have discovered that an old drug, thioridazine, previously prescribed for cases of psychosis and schizophrenia may have an extraordinary new use - “killing” elusive cancer stem cells believed to be responsible for tumour growth, while leaving ordinary human stem cells unharmed.
The existence of cancer stem cells was a relatively recent discovery. Previously, scientists believed that cancer was the product of cell mutation. However in the 1990s, Canadian researches, including Dr. John Dick, identified the presence of cancer producing stem cells in leukemia, and brain and breast cancers. Generally speaking, cancer stem cells operate similar to normal human stem cells with one crucial difference. While human stem cells replicate and “differentiate” into a variety of different cells, cancer stem cells do not differentiate but continuously self-replicate causing deadly tumour growth. Despite knowledge of the existence of cancer stem cells, scientists struggle with two major issues.
First, traditional cancer treatments are largely ineffective against cancer stem cells. After chemotherapy or radiation has eliminated cancerous cells, cancer stem cells linger in the body and resume production of the cancerous cells, resulting in recurrence. Second, chemotherapy and other cancer treatments can be described as somewhat blunt in their operation due to their toxic side effects. Not only do they target and eradicate cancerous cells, but normal human stem cells are also negatively impacted by the treatments. Here is a helpful animation of the issues.
The Canadian team of scientists led by Dr. Mickie Bhatia, believed that chemical compounds existed which could selectively target cancer stem cells. More specifically, they were in search of compounds which would react to the cancer stem cells and induce differentiation, causing the cells to produce ordinary progenitor cells, and cease self-replication. With the assistance of a robotic testing system which screened hundreds of compounds, they discovered that the drug thioridazine, along with approximately 26 others, may accomplish this very feat. In laboratory testing of acute myeloid leukemia, they combined thioridazine with traditional drugs and found the combination to be 55 times more effective at “killing” the cancerous cells, without the harmful side effects associated with traditional treatments. Dr Terry Sachlos, co- investigator and lead author of the publication, says: "By targeting the rare population of cancer stem cells that initiate tumor growth we hope to kill the root of the tumor and prevent it from coming back."
In seeking to understand the effectiveness of thioridazine, the team may have made another important discovery. Thioridazine was developed in the 1960s and sold in Canada as Mellaril. It was prescribed as an anti-psychotic drug and used to treat psychosis, schizophrenia and Parkinson’s disease. The drug operated by blocking dopamine receptors in the brain, which led Dr. Bhatia and his team to make another discovery – cancer stem cells, unlike normal human stem cells, have dopamine receptors. This finding is also potentially significant because the team believes that dopamine receptors may serve as a biomarker for cancer detection.
Not surprisingly, these potentially lifesaving discoveries have been widely reported both internationally and within Canada. Observers remain cautiously optimistic because testing remains in its early (murine) stages. Furthermore, the drug thioridazine is not without safety risks. In the 2000s, evidence emerged that thioridazine may have dangerous side effects including causing irregular heart rhythm. In 2005, Health Canada withdrew thioridazine from the market, and the American FDA permits its use only in severe cases of schizophrenia as a last resort. However, Mr. Bhatia believes the drug will be safer for cancer patients because they would be administered the drug for short periods of about 30 days, rather than years. The team is expecting to receive Health Canada approval to begin human clinical trials of leukemia patients who have not responded to traditional treatments in both Hamilton and another Ontario cancer centre within the year.
In the meantime, the SCC-RI are hoping their initial discoveries will serve as a platform for the identification of more drugs which share the same cancer “killing” properties as thioridazine, and investigating whether their initial positive results with leukemia can be reproduced in other forms of cancer.
Ken Anderson is a JD Candidate at Osgoode Hall Law School.