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.
3 Responses
What do you think that the legal (patent) implications will be on the drug if the clinical tests are successful? Assuming that Health Canada will allow the drug to be put back on the market for leukemia treatment, will it be allowed in its present form? Or will an opportunistic pharmaceutical company tweak the recipe slightly, claiming to mitigate the cardiac implications of its present form, in order to corner the market on the cancer treatment?
The patent wars in big pharma seem to control the market, and often to the detriment of patient care. Hopefully this will not be the case if this drug is found to be an effective means of treating leukemia. It will also be interesting if it will promote more R&D into secondary uses of other patent-expired drugs, which may serve the greater good of public health.
I am uncertain as to the patent implications should the clinical trials be successful. As we know, the scope of the patent monopoly is not a byproduct of the invention itself in the abstract, but rather the purposive construction of its claims as interpreted by the POSITA.
This means that the limited monopoly protected for this invention is practically dependent upon the skill of its drafters. It is therefore entirely possible that a pharmaceutical company could tweak the reciple slightly in order to carve out its own niche, it depends upon what has been claimed.
That being said, I am unsure if I would label such tweaking “opportunisitic” in the first place if it was to meet the other essential elements of patent validity (non-obviousness, utility, etc), and actually diminish health risks. One might be inclined to argue however that such a tweaking is not useful, should Dr. Bhatia’s prediction come true, and it turns out that administration of the drug in short periods of time does not produce the same harmful results as in the past – thus such an innovation would be irrelevant.
I agree further research into secondary uses ought to be encouraged, if it may serve the greater good of public health. I think this is a more interesting case where the primary use turned out to be dangerous. I suppose the question is, whether this new administration of thioridazine (smaller doses) is sufficient in and of itself to eliminate all health risks, and thus minimize the danger of zealous pharmaceutical companies you have identified.
With regard to thioridazine, its safety in this very sick population will be important. Its major side effect is on the heart, and its ability to cause disturbances in the electrical conduction system of the heart, This is a dose related phenomena, so if they must use high doses of thioridazine, it may become an issue, even in short duration use of 30 days. But remember, AML is a deadly illness, so side effects are tolerated more so in this situation, as compared to chronic illnesses like schizophrenia, for which thioridazine was originally used for.
This is a very interesting Intellectual property situation.
2 points i would like to bring up….
1) Thioridazine has a long history in the medical literature of its anti-cancer properties. Specifically, in 2004, a group in Japan reported that thioridazine causes cell death, “apoptosis”, in leukemia cell lines, “Phenothiazines suppress proliferation and induce apoptosis in cultured leukemic cells without any influence on the viability of normal lymphocytes.”
Of the group of phenothiazines they tested, they found thioridazine to be the most potent anti leukemia agent.
Will patent examiners be comfortable with the distinction between a treatment for a leukemia cancer stem cell vs a treatment for a leukemia cancer cell, with regard to its use?
Since in the case of thioridazine it seems to have significant effect on both.
The current discovery of its differentiating action on cancer stem cells, is novel, but how does one separate its other mechanism, in that it kills non-stem cell leukemia cells.
If leukemia patients do respond positively to thioridazine treatment, is it due to its effect on a stem cell, or due to its effects on the rest of the leukemic cancer cells? Probably both?
2) Thioridazine is off patent and available in generic form in many jurisdictions outside of Canada, including the USA, the largest pharma market in the world. This is an important issue, as the re-purposing of old drugs is becoming a significant area of research.
Furthermore…
If the effect of thioridazine on cancer stem cells is mediated through the dopamine receptors, as elegantly demonstrated by the authors, there are many dopamine receptor antagonists on the market, with a much safer side effect profiles than thioridazine, and most are off patent or soon to be off patent, and cheap generics available. Would it not make sense to test safer dopamine receptor antagonists in cancer animal models and eventually patients? If safer dopamine receptor antagonists are found to also have such cancer stem cell effect, and are available as a cheap generic, more problems, no? How does one control the market if a physician can write a prescription for the cheap generic version of a drug?
Important implications here, as the cost of taking a drug to market, and getting FDA approval, is in the hundreds of millions of dollars.
Can investment capital be raised to start this process without knowing if a thioridazine “use” patent is granted, for that matter how does one attract a large pharma partner without solid IP protection, and the inability to prevent a physician from prescribing a cheap generic, regardless of, if a “use” patent is granted.
New uses for old drugs, may therefore best be developed with public money, for the public good. The IP issues, and the inability to guarantee the significant revenues needed to justify the high development costs, if cheap generics are available, seem complicated.
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