Part 1 of 3
The development of TKIs (tyrosine kinase inhibitors) a decade ago revolutionized the treatment of CML. These medications (Gleevec, Sprycel, Tasigna, Bosulif and Iclusig) all work to inhibit the proliferation of leukemic cells. In some people, the disease may be so well suppressed that it amounts to a cure – with no detectable leukemia even after the person stops taking the drug. In trials where people have stopped taking a TKI, about 25% showed no evidence of CML afterward (Rea and colleagues. Blood 2012;120:916). Another 15% had low-level evidence of CML but no worsening of the disease, suggesting that a true cure (complete elimination of CML) may not be necessary because the body’s immune response (which detects abnormal cells) can keep things under control.
Why don’t more people achieve an actual cure? The answer lies deep in the bone marrow. CML is usually caused by a mutation that results in a cancer gene called BCR-ABL. This gene produces signalling proteins (called transcripts) that turn on various pathways that cause white blood cells (WBCs) to proliferate. TKIs act by blocking these signals. But they can’t get at the root of the problem – the stem cells where CML originates. Leukemic stem cells can go into a quiescent phase, in effect laying low and avoiding detection, and are remarkably resistant to TKIs (Graham and colleagues. Blood 2002;99:319-325). These quiescent stem cells can be detected even after a person has achieved a complete cytogenetic response (CCyR) with Gleevec and their disease is otherwise in full retreat (Bhatia and colleagues. Blood 2003;101:4701-4707). The same is true with more potent second-generation TKIs (Tasigna, Sprycel). BCR-ABL may be completely inhibited, but leukemic stem cells can still be found hiding in the bone marrow (Copland and colleagues. Blood 2006;107:4532-4539; Konig and colleagues. Leukemia 2008;22:748-755).
What this means is that leukemic stem cells are not “addicted” to BCR-ABL (Ahmed & Van Etten. Hematology Am Soc Hematol Educ Program 2013;2013:189-200). That is, leukemic stem cells are not completely dependent on BCR-ABL to survive. So killing off the leaves (the BCR-ABL transcripts with a TKI) will not kill the stem. To achieve the goal of killing leukemic stem cells, other approaches – and additional therapies – are needed. The challenge is the complexity of leukemia, but this very complexity also provides numerous targets for new treatments in development. And part of the answer may boil down to some simple things – such as pain relievers, red wine and fish oil (but more on that later).
Stopping the signals
The cancer gene BCR-ABL acts by sending a signal that promotes the proliferation of WBCs. But this signal is only one of many. Other signals also support the survival of leukemic stem cells. To use an analogy, the FM signal may be broadcasting to the WBCs, but the ham radio in the corner is picking up other messages, and these are the ones that must be blocked to shut down the leukemic stem cells. But the ham radio has many frequencies or signalling pathways, so that challenge is to figure out which are the leukemia signals, which are normal messages to healthy blood cells, and which are just background noise.
So let’s turn our attention to two of these pathways.
The first is called JAK-STAT (for Janus kinase-Signal Transducer and Activator of Transcription), which acts as an On switch for certain genes. It’s known that BCR-ABL cells turn on this pathway (Ilaria and colleagues. J Biol Chem 1996;271:31704-31710), but it isn’t clear what signals are getting sent. Drugs that block this activity (called JAK2 inhibitors) have been shown to cause the death of cells containing BCR-ABL (Samanta and colleagues. Oncogene 2009;28:1669-1681), and there’s some preliminary evidence that combining a JAK2 inhibitor with Gleevec may kill off early leukemic cells as well (Chen and colleagues. J Natl Cancer Inst 2013;105:405-423). An encouraging aspect of this line of inquiry is that a JAK2 inhibitor, ruxolitinib, is already being used to treat myelofibrosis, so this should speed up the research. Several phase I/II trials are now underway investigating ruxolitinib in combination with Tasigna.
Another potential target is catenin (also called beta-catenin), a protein “switch” that turns on certain genes. Abnormal beta-catenin expression is associated with many forms of cancer, such as liver, lung, breast and ovarian cancer. Normal blood stem cells don’t appear to need beta-catenin, but leukemic stem cells that are resistant to Gleevec do appear to need it to survive (Heidel and colleagues. Cell Stem Cell 2012;10:412-424). So researchers are now looking at treatments that can inhibit beta-catenin. Curiously enough, one drug that has been shown to inhibit beta-catenin and kill off leukemic stem cells in preliminary testing is indomethacin, a pain reliever sold under various trade names (Indocid, Metindol, Arthrexin, and others). Indomethacin is one drug in the category of non-steroidal anti-inflammatory drugs (NSAIDs), which includes Aspirin, Motrin/Advil, and Aleve. While it’s important to emphasize that these drugs have not been tested in CML, there’s the intriguing possibility that a common, household pain reliever may play a role in the future in combatting CML.
We’ll look at other potential targets (and red wine) in Part 2 of this article.