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Source: Thailand Medical News  Oct 17, 2019  4 years, 5 months, 1 week, 4 days, 8 hours, 46 minutes ago

New Treatment Protocol To Eliminate Leukemia Cancer Stem Cells

New Treatment Protocol To Eliminate Leukemia Cancer Stem Cells
Source: Thailand Medical News  Oct 17, 2019  4 years, 5 months, 1 week, 4 days, 8 hours, 46 minutes ago
A team of medical researchers from the University of California, Los Angeles have developed a new treatment protocol to eliminate leukemia stem cells in patients undergoing remission after treatment with conventional drugs.
new-treatment-protocol
Leukemia Stem Cells


In 2001, the introduction of the drug imatinib revolutionized the treatment of a type of cancer called chronic myelogenous leukemia. In more than 80 percent of people with CML who received the drug, the disease went into complete remission. However,  the cancerous stem cells remain in the body for years after their cancer has gone into remission. If treatment with imatinib or another similar medication is stopped and in some cases, even while treatment continues, the stem cells can cause cancer to recur.

Presently, in studies in animal models as well as isolated human cancer cells, UCLA researchers have discovered a way to eliminate the CML stem cells. Their approach uses an antibody to block a protein that the stem cells rely on to grow. The advance, described in a study published in the Journal of Clinical Investigation, might eventually help treat not only chronic myelogenous leukemia but other cancers as well.

Imatinib, commonly marketed under the brand name Gleevec, is a tyrosine kinase inhibitor; it works by targeting the genetic abnormality that causes chronic myelogenous leukemia.

Dr. John Chute, the study's senior author commented in a phone interview with Thailand Medical News, “Our results suggest that it may be possible to eradicate CML stem cells by combining this new targeted therapy with a tyrosine kinase inhibitor.This could lead to a day down the road when people with CML may not need to take a tyrosine kinase inhibitor for the rest of their lives."

Chronic myelogenous leukemia causes the bone marrow to produce too many white blood cells. More than 95 percent of all cases are caused by the same genetic change, a mashup of two genes that are normally located on different chromosomes. Imatinib targets that "fusion gene." Imatinib isn't a permanent cure in most cases, however.

Dr Chute, who is also a professor of medicine and radiation oncology at the David Geffen School of Medicine at UCLA and a member of the UCLA Jonsson Comprehensive Cancer Center further added in the phone interview, "In the majority of people, the CML stem cells are still there. Several studies have shown that even after years on imatinib, when people stop treatment, their cancer has a significant likelihood of recurrence.”

In the last few years, Chute and his colleagues have shown that a molecule called pleiotrophin, which is produced by the bone marrow, supports normal blood stem cell growth and recovery from stress. They wondered whether pleiotrophin might also play a role in the survival of chronic myelogenous leukemia stem cells. 

The team studied animal models that had the CML-causing fusion gene. Normally, those mice quickly develop symptoms of ch ronic myelogenous leukemia and live for an average of just three to four months. But mice with the CML-causing gene that lacked the pleiotrophin gene had normal levels of white blood cells and survived for nearly twice as long.

The medical researchers then transplanted blood stem cells from the group of mice with the CML-causing gene into previously healthy mice, and the new mice contracted chronic myelogenous. When the researchers tried the same experiment using blood stem cells from the mice that lacked pleiotrophin, the transplant recipients showed little evidence of  leukemia and their levels of the cancer-causing gene were less than 1 percent of the levels found in the control group of mice.

Upon isolating CML stem cells from humans with the cancer, the team  discovered that the cells had 100 times the levels of pleiotrophin found in healthy blood stem cells. Further experiments revealed that the CML cells were producing their own pleiotrophin in addition to reacting to the pleiotrophin that's normally in the body.This provides an example of cancer stem cells that are perpetuating their own disease growth by hijacking a protein that normally supports the growth of the healthy blood stem cells.

When the team used an anti-pleiotrophin antibody to block pleiotrophin in isolated human cancer cells, the CML stem cells began to die. Further experiments revealed that in the CML stem cells, pleiotrophin acts by triggering a known mechanism that keeps cells alive. When pleiotrophin is blocked by antibodies, it can't activate this mechanism and the CML stem cells die. Normal cells can proliferate and survive without pleiotrophin.But human CML stem cells are relatively addicted to pleiotrophin and don't survive well without it.

To assess its therapeutic potential, Chute's group tested the effect of combining imatinib and the anti-pleiotrophin antibody. Together, the drugs virtually eliminated human CML cells that had been transplanted into mice. The anti-pleiotrophin antibody was used in preclinical studies only and has not been tested in humans or approved by the FDA as safe and effective for use in humans.

The researchers now are working on modifying the anti-pleiotrophin antibody to make it more similar to antibodies produced by humans, which would make them less likely to be rejected by the human immune system.

A final product for further animal models and lab studies would be ready before the ed of the year with human clinical trials anticipated to start sometime in mid 2020.

Reference: 

Heather A. Himburg et al. Chronic myelogenous leukemia stem cells require cell-autonomous pleiotrophin signaling, Journal of Clinical Investigation (2019). DOI: 10.1172/JCI129061
 

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