I’ve spent a number of posts going on and on about how targeting cancer stem cells (CSCs) is the next big thing for cancer therapies, and how important it is that we study and learn all we can about them (know your enemy, right?). All of this has probably left you with at least two questions: why doesn’t the ‘regular’ therapy work on CSCs; and, what has been done about it?
Here is my take on why some cancer researchers think CSCs should be therapeutic targets, and what they have found so far.
Why doesn’t the conventional therapy work on CSCs?
The first thing to know is how chemotherapies typically work. Chemotherapies (chemo) work by reducing a cell’s ability to divide and proliferate. Different drugs have different mechanisms of action (see table), so using several drug types can maximize their anti-proliferative effects (known as combination therapy). The more often a cell divides, the more susceptible it becomes to the effects of the chemotherapy. Since rapid, uncontrolled cell division is the essence of cancer, these anti-proliferative agents are ideal. Side note: this is why one of the side effects of chemo is hair loss: the normal cells producing hair divide frequently, and so are also affected by the chemo.
For the most part, these therapies (especially in combination) are very successful, and can lead to a cure. However, occasionally there is relapse or metastasis of the disease. Proponents of the CSC model of cancer development suggest that this regrowth is due to a chemo-resistant population of cancer cells: the CSCs.
Now, to answer your question: CSCs are believed to avoid the effects of chemotherapy by not dividing frequently. Wait, what? You just said cancer is rapidly dividing cells, CSCs are cancerous, so…? Both of those points are true, but they are not mutually exclusive. Remember CSCs are cancer stem cells, meaning they are cancerous and they also possess the capabilities of stem cells (differentiation, self-renewal, etc.). They are also thought to have the stem cell property of becoming quiescent, which is a state of inactivity or hibernation (i.e. not dividing). If the CSCs are not dividing often, they could avoid the effects of chemo, and reproduce the cancer over time.
Another way that CSCs can escape the effects of chemotherapy is to pump out the drug. In fact, some of the markers that researchers use to identify CSC populations are ATP-binding cassettes and aldehyde dehydrogenase: enzymes that act as efflux pumps, and are used to pump ‘unwanted’ chemicals (i.e. chemo) out of the cell. If the drug can’t stay inside the cell, it certainly isn’t going to be able to kill it!
So, where do we currently stand?
Before I get to that, generating CSC-specific therapies is easier said than done. As I discussed last time, there are many similarities (functionally, genetically, and molecularly) between cancer stem cells and normal stem cells. This makes targeting only the cancer stem cells difficult, since we certainly don’t want to destroy the normal ones!
This issue is particularly challenging in blood-based (hematological) cancers like leukemia. Hematopoietic stem cells (HSCs) – normal blood stem cells – are needed to produce essential blood cells: white blood cells for infection, red blood cells for carrying oxygen, and platelets for clotting – all of which have a relatively high turnover rate. Destroying the HSC population would reduce an individual’s ability to make these cells, risking the individual’s health.
But if there’s one thing I have learned about scientists, it’s that they love a challenge!
None more so than the Bhatia group at McMaster University (I may be a little biased though!). In 2012, Dr. Mickie Bhatia and his team published a paper in Cell identifying a drug that was able to selectively target the leukemia stem cells (LSCs), leaving the HSC population alone.
To identify this drug, the group took a multi-step approach. They first wanted to find drugs that were able to induce differentiation in CSC populations. In other words, take away their stem-like properties, making them ‘normal’ cancer cells. Using high-throughput screening methods (techniques that allow researchers to analyze the effects of many drugs/compounds at once), a panel of 590 compounds was narrowed down to two candidate drugs.
The next step in the process was to determine if the two candidates could discriminate between normal stem cells and CSCs. While both drugs affected both the normal and cancerous stem cells, at a particular dosage, one of the drugs was able to preserve the majority of normal stem cell function, while strongly inducing differentiation in the CSCs: thioridazine.
Interestingly, thioridazine is a compound currently used to treat psychosis and schizophrenia. But what I personally found the most interesting, is when the researchers tried using thioridazine in combination with a drug commonly used to treat leukemia: cytarabine.
While cytarabine is relatively effective at treating leukemia, it can be quite toxic, and does not discriminate between normal and cancer cells (hooray for equality?). However, when Bhatia’s team combined thioridazine and cytarabine in leukemic samples, they were able to lower the amount of cytarabine needed for therapeutic effect. This means that they successfully reduced the toxicity to normal cells, preserved the HSCs, and eliminated the LSCs.
The moral of the story is that it can be done! With the right tools and approach, CSC researchers can selectively target CSCs, and leave the normal stem cells largely unaffected. Of course, the next levels of testing (in vivo, and clinical trials) remain hurdles to be overcome, but we can be optimistic. What’s more, not only might we be able to reduce the potential for disease relapse and metastasis, but we may also be able to reduce some of the side effects and toxicity of current therapies. In this ideal future, everyone wins, well, except for the cancer stem cells.
Sara M. Nolte
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