Part 3 of 3
TKIs (tyrosine kinase inhibitors) have been highly successful in the treatment of CML, controlling the proliferation of white blood cells by blocking the action of the BCR-ABL cancer gene. But the story doesn’t end there. TKIs have enabled many people to manage their illness as a chronic condition – like high blood pressure or diabetes – and live a normal lifespan. But however effective, TKIs are generally not considered to be a cure.
So there’s room for improvement, and researchers are continually exploring new ways to interfere with the CML disease process. A key target is leukemic stem cells, which harbor the disease despite the best efforts of the TKIs. Leukemic stem cells are hardy seeds of disease that can cause a relapse, such as when someone stops taking their medication. So an important goal is to identify ways of killing these cells so a person can be truly leukemia-free.
In the first two parts of this article we looked at how novel therapies in development may interfere with biological pathways in the body that promote CML. In part 3, we’ll explore the curious connections between CML, asthma and fish oils.
The story begins with arachidonate, an omega-6 polyunsaturated fat that got its name from the peanut (arachis, in Latin). Our main sources of it are meat, dairy products and eggs (rather than peanut oil, which is a saturated fat), although our bodies can also synthesize it. Arachidonate is an important component of cell walls, muscle, and brain tissue. But it also plays a key role in the formation of a wide range of compounds in the body.
The body uses arachidonate to create a family of signalling molecules called eicosanoids, which are involved in inflammation and the functioning of the immune system. A gene called Alox5 codes for an enzyme (5-LO) that ultimately leads to the creation of a bad actor called leukotriene-4, which promotes inflammation, nerve degeneration and cancer.
How does this relate to CML? An interesting finding is that the Alox5 gene is turned on in leukemic stem cells (Radich and colleagues. PNAS 2006;103:2794-2799). This suggests that this pathway is somehow involved in the disease process and could be a target for treatment.
Thus far, laboratory studies have found that inhibiting the 5-LO enzyme that creates leukotriene-4 resulted in the destruction of CML cells (Anderson and colleagues. Leuk Res 1995;19:789-801). A study in animals then showed that knocking out the Alox5 gene blocked the action of leukemic stem cells: the CML gene (BCR-ABL) was still present, but it could not induce CML (Chen and colleagues. Nat Genet 2009;41:783-792).
These results suggested that the 5-LO enzyme or the Alox5 gene might be good targets for treatment. As it turned out, a 5-LO inhibitor was already available on the market as zileuton (Zyflo), a medication that is used to treat asthma. In asthma, leukotrienes cause muscle contractions and inflammation in the lungs, and zileuton blocks these effects. So zileuton was re-purposed to see if it had any effects in CML (Chen and colleagues. Cell Cycle 2009;8:3488-3492). A preliminary study in animals found that Gleevec was better than zileuton in reducing white blood cell counts, but zileuton provided the added advantage of killing off leukemic stem cells. The combination of zileutron and Gleevec appeared to be even better still (Chen and colleagues. Anticancer Agents Med Chem 2010;10:111-115). A phase I trial in the U.S. will examine the potential benefits of combining zileuton and Sprycel (NCT02047149 at clinicaltrials.gov). The study is currently recruiting people so no results are available yet.
A parallel area of research is looking at related compounds, such as omega-3 polyunsaturated fats. Of particular interest is PGJ3 (delta12 prostaglandin J3), which is formed from the breakdown of omega-3. Omega-3 fatty acids have a number of health benefits. The main sources are fatty fish, such as salmon, herring and sardines, but they are often added to foods (such as eggs). An interesting property of PGJ3 is that it’s toxic to leukemic stem cells but not to healthy stem cells, so it has the potential to sift through the bone marrow and destroy any diseased cells it finds (Hegde and colleagues. Blood 2011;118:6909-6919).
This research is still very preliminary. What what makes it intriguing is that PGJ3 is naturally produced by our bodies from EPA (eicosapentaenoic acid), one of the components of fish oils and available as a dietary supplement. It’s too early to say if fish oil supplements will have any effect on CML. And it’s important to note that the maximum recommended amount of EPA (and DHA, another omega-3) from supplements is 2 grams per day. As with other dietary supplements, it’s unclear if nutritional amounts of fish oils can be raised to pharmaceutical levels to achieve a therapeutic effect in CML.
There are many avenues of research, and many potential paths to a cure for CML. While many of these investigations are in their infancy, it is likely that one or more of these approaches will be able to build on success of the TKIs in the future and further improve the health and wellbeing of people living with CML.