Inhibition of the protein Ezh2 causes chronic myelogenous leukemia (CML) stem cells to die. Adding drugs that target this protein to imatinib (Gleevec) or other BCR-ABL blockers could result in a cure for this disease, according to research published in the journal Cancer Discovery.1
Despite the success of targeted therapies such as imatinib in managing chronic myelogenous leukemia (CML), complete eradication of the leukemia cells is achieved in only 10% to 20% of patients. The remaining patients retain a reservoir of leukemia stem cells, which can re-initiate the disease, and must continue treatment for the rest of their lives.
Furthermore, many patients develop drug resistance to imatinib and other drugs that block BCR-ABL, the fusion protein that drives growth of the disease, over time, and the drugs lose their effectiveness. In addition, not all patients will benefit from second-line and third-line targeted therapies, or they develop severe side effects.
Researchers at Dana-Farber Cancer Institute and Boston Children’s Hospital found that leukemia stem cells have an overabundance of the protein Ezh2, which helps them survive and develop full-fledge CML cells. Follow-up studies in mice demonstrated that Ezh2 inhibition resulted in CML stem cell death, thereby destroying the source of the disease.
Stem cell dependence on Ezh2 suggests that drugs targeting the protein would be effective treatments. Drugs that target Ezh2 protein are currently in clinical trials for other cancers. Dana-Farber/Boston Children’s is a site in a multicenter phase 1 trial of an Ezh2 inhibitor for children with rhabdoid and other tumors.
Combining Ezh2 blockers with imatinib or similar drugs could provide an effective cure for some patients. However, Ezh2 inhibitors are likely to be tested first in patients who do not respond initially to imatinib and other similar therapies or after resistance develops.
“Our findings suggest inhibition of Ezh2 should be considered as a way to eradicate CML when used in combination with current targeted therapies. It offers a promising approach to shortening the duration of therapy in order to achieve a cure. If successful, the cost savings of such an approach could also be significant,” the authors conclude.2
1. Xie H, Peng C, Huang J, et al. Chronic myelogenous leukemia initiating cells require Polycomb group protein EZH2. Cancer Discov. 2016 Sep 14. doi: 10.1158/2159-8290.
2. Discovery offers prospect of shorter treatment and cure for chronic myelogenous leukemia [news release]. EurekAlert! web site. https://www.eurekalert.org/pub_releases/2016-09/dci-dop090816.php. Published September 14, 2016. Accessed September 21, 2016.