Navigation Links
Study reveals need for personalized approach in treatment of AML
Date:5/15/2011

WINSTON-SALEM, N.C. Monday, May 16, 2011 A new discovery in mice by researchers at Wake Forest Baptist Medical Center may one day allow doctors to spare some patients with acute myeloid leukemia (AML) from toxic treatments, while also opening the door for new therapeutic research.

AML, the most common form of acute leukemia seen in adults, is an aggressive form of cancer that primarily affects the elderly. Despite years of research, outcomes for most patients remain poor, particularly for one subset of patients with a specific mutation of the FLT3 receptor.

At a microscopic level, each cell's surface is covered in proteins that allow for signals on the outside of a cell to "turn on" various activities inside that cell. FLT3 is one of those receptor proteins. Mutations of the FLT3 receptor are among the most common mutations seen in the disease affecting about 20 to 30 percent of AML patients and have been associated with worse prognosis.

A new study, published recently in the journal Experimental Hematology, reveals that one particular mutation of the FLT3 receptor, called internal tandem duplication (ITD), alters the patient's responsiveness to standard therapy.

"This research uses a mouse model to define the changes in chemotherapy response that the presence of the FLT3-ITD causes," said Timothy S. Pardee, M.D., Ph.D., an assistant professor of hematology and oncology and lead author of the study. "While its affect on prognosis has been well documented, its affect on therapy response has been poorly understood."

Pardee and colleagues used mice that had leukemia, either with or without the FLT3-ITD, to examine the effects of the mutation on responsiveness to two drugs used in combination as standard chemotherapy treatment for AML patients: cytarabine and doxorubicin. Both drugs work by altering the DNA of cells in different ways, causing them to essentially commit suicide.

The researchers found that the presence of the FLT3-ITD mutation makes cells resistant to doxorubicin, but makes them extra sensitive to cytarabine, when the drugs are administered separately. More importantly, the mutation causes the cells to be resistant overall to the combination of the two drugs, the most common clinical application.

When the mutation occurs, it is a cancer-initiating event. The receptor is no longer able to turn itself off, so it continuously signals the cells to grow and repair damage, such as the damage intentionally caused by doxorubicin.

"The mice who had this mutation seemed to be able to repair certain kinds of DNA damage, specifically, the double strand DNA breaks that the doxorubicin creates," Pardee said. "The FLT3-ITD mutation is telling the cell to repair itself at a pace that keeps up with the amount of damage the drug is designed to cause. If you have a cancer cell that you're trying to kill by doing a certain type of damage and that cell is better at repairing that kind of damage, you have to do more damage to get the cell to die. The mice that were treated with just doxorubicin died at the same rate as those that received no treatment at all."

And, while the FLT3-ITD mutation seems to make cells more sensitive to the impact of cytarabine when exposed to just the one drug, the mutation lessens the impact of the combination of the two drugs together.

"It's almost like the doxorubicin is protecting the cancer cells somewhat from the impact of the cytarabine, which is trying to kill the cell," Pardee said. "When this mutation is present, there is no benefit to adding the doxorubicin. The amount of leukemia does not lessen with the use of it."

Doxorubicin falls into a class of extremely toxic drugs known as anthracyclines. As with other chemotherapy agents, they are known to cause hair loss. However, they are also known to suppress normal cells in the bone marrow and to cause cardiac toxicity. Treatment with drugs of this class can directly injure the heart muscle and sometimes even cause heart failure, Pardee explained.

"Virtually every AML patient in America and Europe who can handle this combination of drugs will receive this standard treatment under current practice guidelines," Pardee said. "More studies are needed to determine the applicability of these findings in humans, but this study shows, in an animal model, that those with the FLT3-ITD mutation are deriving no benefit from the addition of doxorubicin.

"We're hopeful that in the future, these findings will lead to more personalized patient care," he said. "The 'one-size-fits-all' approach to treating AML needs to be re-examined."

In addition to investigating ways to personalize approaches in treatment, Pardee said that future research may focus on developing drugs that can be combined with cytarabine in patients with this mutation and be effective, perhaps by inhibiting the FLT3 receptor or working in ways other than creating double strand DNA breaks.


'/>"/>

Contact: Jessica Guenzel
jguenzel@wakehealth.edu
336-716-3487
Wake Forest Baptist Medical Center
Source:Eurekalert

Related biology news :

1. Study finds therapies using induced pluripotent stem cells could encounter immune rejection problems
2. Oregon Farm to School bill would benefit health through job creation, study finds
3. Study shows evolutionary adaptations can be reversed, but rarely
4. MIT Study: conventional fossil fuels sometimes greener than biofuels
5. Clemson University institute to study vertical farming feasibility in Charleston, S.C.
6. Study: Pace of brain development still strong in late teens
7. WSU study expands time window for facial nerve rehabilitation
8. iPhone can diagnose stroke: study
9. Study probes sources of Mississippi River phosphorus
10. BC scientists link to European Consortium studying human genome
11. Study shows corn gene provides resistance to multiple diseases
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:5/16/2016)... , May 16, 2016   EyeLock LLC , ... announced the opening of an IoT Center of Excellence ... and expand the development of embedded iris biometric applications. ... level of convenience and security with unmatched biometric accuracy, ... identity aside from DNA. EyeLock,s platform uses video technology ...
(Date:4/28/2016)... SAN FRANCISCO and BANGALORE, India ... part of EdgeVerve Systems, a product subsidiary of Infosys (NYSE: ... service provider, today announced a global partnership that ... convenient way to use mobile banking and payment services. ... Mobility is a key innovation area for financial services, but ...
(Date:4/19/2016)... 20, 2016 The new GEZE ... compact web-based "all-in-one" system solution for all door components. ... or the door interface with integration authorization management system, ... systems. The minimal dimensions of the access control and ... building installations offer considerable freedom of design with regard ...
Breaking Biology News(10 mins):
(Date:6/27/2016)... ... June 27, 2016 , ... Parallel 6 , the ... today the Clinical Reach Virtual Patient Encounter CONSULT module which enables both ... physician and clinical trial team. , Using the CONSULT module, patients and physicians can ...
(Date:6/27/2016)... ... June 27, 2016 , ... ... will join the faculty of the University of North Carolina Kenan-Flagler Business ... strategy and entrepreneurship at UNC Kenan-Flagler, with a focus on the school’s international ...
(Date:6/27/2016)... --  Ginkgo Bioworks , a leading organism design ... awarded as one of the World Economic Forum,s ... innovative companies. Ginkgo Bioworks is engineering biology to ... in the nutrition, health and consumer goods sectors. ... including Fortune 500 companies to design microbes for ...
(Date:6/24/2016)... SAN DIEGO , June 24, 2016 /PRNewswire/ ... that more sensitively detects cancers susceptible to PARP ... individual circulating tumor cells (CTCs). The new test ... of HRD-targeted therapeutics in multiple cancer types. ... therapies targeting DNA damage response pathways, including PARP, ...
Breaking Biology Technology: