Elimination of Beta-Catenin After Imatinib Treatment Kills Leukemia Stem Cells

AJs are necessary for the creation and maintenance of epithelial cell layers by regulating cell growth and adhesion between cells. Beta-catenin also anchors the actin cytoskeleton and may be responsible for transmitting the contact inhibition signal that causes cells to stop dividing once the epithelial sheet is complete. The gene that codes for beta-catenin can function as an oncogene. An increase in beta-catenin production has been noted in those people with basal cell carcinoma and leads to the increase in proliferation of related tumors.

Imatinib was the first of a new class of drugs that act by specifically inhibiting a certain enzyme – a receptor tyrosine kinase – that is characteristic of a particular cancer cell, rather than nonspecifically inhibiting and killing all rapidly dividing cells. Imatinib was a model for other targeted therapies that inhibited this class of enzymes. It is used in treating CML, gastrointestinal stromal tumors (GISTs) and some other diseases. By 2011, imatinib had been approved by the [US] Food and Drug Administration to treat ten different cancers.

In CML, the tyrosine kinase enzyme ABL in white blood cells is locked in its activated form. This causes the excessive proliferation and high white blood cell count, which is characteristic of the disease. Imatinib binds to the site of tyrosine kinase activity and prevents its activity, causing apoptosis.

Investigators at Harvard Medical School (Boston, MA, USA) reported in the April 1, 2012, issue of the journal Cell Stem Cell that they used a conditional mouse model to show that deletion of beta-catenin after CML initiation did not lead to a significant increase in survival. However, deletion of beta-catenin combined with imatinib treatment to delay disease recurrence after imatinib discontinuation and to abrogate CML stem cells.

These effects could be mimicked by pharmacologic inhibition of beta-catenin via modulation of prostaglandin signaling. Treatment with the cyclooxygenase inhibitor indomethacin reduced beta-catenin levels and led to a reduction in leukemia stem cells. Thus, inhibiting beta-catenin by genetic inactivation or pharmacologic modulation was an effective combination therapy with imatinib and targeted CML stem cells.

"Imatinib inhibits the oncoprotein that drives CML and it is incredibly effective at putting patients into remission," said senior author Dr. Scott Armstrong, professor of oncology at Harvard Medical School. "But there is growing evidence that this does not rid the body of the most immature cancer cells. The question is how can we eradicate those cells? The appeal is that this pathway is important for the leukemia, but not for normal cells. It gives us an angle for therapy. A drug targeted at beta-catenin might just get rid of leukemia and its stem cells once and for all, while leaving healthy blood stem cells unscathed."

"It will take time because people with CML already do pretty well," said Dr. Armstrong. "But beta-catenin inhibitors might be just what the doctor ordered in the case of some other, harder-to-treat forms of leukemia, in colon cancer, or perhaps in patients who have entered an acute stage of CML."

Related Links:
Harvard Medical School