December 10, 2015 | by Chase Doyle
Sometimes, just a few remaining cancer cells can mean the difference between remission and relapse. For patients with aggressive bone marrow disease such as acute myeloid leukemia (AML), this distinction can be deadly.
City of Hope researchers are determined to eliminate those remaining cancer cells and, in doing so, improve patient survival. First, however, they must understand how resistance works.
According to a new study featured on the cover of the journal Cell Stem Cell, they’re closer than ever to their ultimate goal – and are now exploring a potential new approach in the fight against AML.
“That’s the challenge in AML treatment,” said Ya-Huei Kuo, Ph.D., Associate professor of the Division of Hematopoietic Stem Cell & Leukemia Research at Beckman Research Institute of City of Hope. “Patients can receive chemotherapy treatment and go into remission, but if there are just a few leukemia stem cells left behind, a relapse can occur, and relapses tend to be resistant to the initial therapy.”
“The key to a cure in leukemia,” Kuo added, “lies in the ability to eradicate leukemia stem cells that are at the root of the disease.”
The Guardian of the Genome
The new research by City of Hope’s scientists began with novel insights into the role of the so-called “guardian of the genome,” the master tumor suppressor protein known as p53. The gene that governs the making of the p53 protein is frequently mutated in many types of cancers, and this promotes both cancer formation and therapy resistance.
In AML, however, genetic mutation of p53 is relatively rare. What researchers at City of Hope were able to describe is how a cancer gene abnormality hijacks the healthy activity of the tumor suppressor, but without mutating the gene.
In patients with AML, abnormality of a specific chromosome, known as “chromosome 16 inversion,” leads to a functional breakdown of this tumor suppressor pathway. As a result, leukemia is allowed to propagate unchecked.
“We identified an enzyme, called histone deacetylase 8 (HDAC8), that modifies and inactivates this tumor suppressor protein in the presence of the oncogenic fusion protein generated by chromosome 16 inversion,” Kuo said.
Exploring Potential Therapies
Thanks to this new insight, City of Hope researchers identified a unique opportunity to restore p53 activity and selectively target the abnormal leukemia cells. Researchers then began testing different drugs to disrupt the HDAC8 enzyme and reactivate p53.
Using an HDAC8 inhibitor, Kuo and colleagues were able to selectively kill the leukemia stem cells that carry this chromosome inversion while still preserving healthy stem cells.
“We took patients’ leukemia cells and engrafted them into mice and treated the leukemia-bearing mice with the HDAC8 inhibitor,” Kuo said. “Very excitingly, mice treated with the drug were essentially cured of leukemia. We didn’t see much regrowth of the leukemia following treatment, indicating that the leukemia stem cells have been eliminated.”
After these promising results, Kuo and her colleagues are now working to adapt this type of treatment to benefit patients who carry the inversion 16 abnormality. About half of the patients with this type of AML would develop relapse and resistance after the initial remission.
Better Drugs Needed
Despite this early success, researchers are still in search of more effective therapies.
“The drug that we have been using is not a clinically approved agent,” Kuo said. “In its current form, we may not be able to achieve the effective doses in patients, so we need to make it more potent. We need to make a better inhibitor.”
Although several HDAC inhibitors have been used in the past, both as treatment and in tests, concerns about toxicity remain, Kuo said.
“If you look at all of the drugs that have been tested before, they are targeting a broad spectrum of HDAC enzymes,” Kuo said. “This is going to affect a lot of normal cell activity and cause significant toxicities.”
Kuo believes it is imperative for researchers to develop inhibitors that target the specific enzymes responsible for a particular abnormality rather than an entire class of enzymes.
“We’re trying to develop a type of drug that’s clinically applicable,” said Kuo. “What that will be, we don’t know yet, but that’s the goal — to eradicate all these stem cells that are at the root of the leukemia.”
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