Featured Research

from universities, journals, and other organizations

New Drug Target Might Sidestep Gleevec Resistance

Date:
September 22, 2006
Source:
Thomas Jefferson University
Summary:
Though enormously successful, the leukemia drug Gleevec has some downsides. Studies have linked the drug to heart failure in a small number of patients, and drug resistance can be a problem. But researchers at the Kimmel Cancer Center at Thomas Jefferson University may have found a new way to sidestep such resistance. They have discovered that by reactivating a protein normally shut off in leukemia and in Gleevec-resistant cancer cells, leukemia development is halted.

Though enormously successful, the leukemia drug Gleevec has some downsides. Recent studies have linked the drug to heart failure in a small number of patients, and drug resistance continues to be a problem. But now, researchers at the Kimmel Cancer Center at Thomas Jefferson University in Philadelphia may have found a new way to sidestep such resistance. They have discovered that by reactivating a protein that is normally shut off in leukemia and in Gleevec-resistant cancer cells, leukemia development is halted.

A drug that could turn on the gene that makes the protein C/EBP-alpha, a "transcription factor" required for cells to differentiate, then, might control or even eliminate the cancer.

According to Bruno Calabretta, M.D., Ph.D., professor of cancer biology at Jefferson Medical College of Thomas Jefferson University, transcription factors are molecular switches that turn on genes when their function is needed. C/EBP-alpha expression is low in leukemia cells such as those with the BCR-ABL protein defect, which causes chronic myeloid leukemia (CML), a disease that Gleevec treats so well.

Gleevec is normally prescribed for patients early on in CML, which is characterized by an overabundance of white blood cells. But when the disease advances to the terminal stage, or "blast crisis" phase, the cells, called blasts, remain undifferentiated and accumulate rather than becoming more mature white blood cells called granulocytes. Gleevec is much less effective in this stage, Dr. Calabretta says. Yet, in leukemia cells that respond to treatment with Gleevec, expression of C/EBP-alpha increases.

The researchers looked at what might happen if C/EBP-alpha was turned back on in blast crisis patients and in CML patients who were resistant to Gleevec. Reporting in the journal Blood, they found that in both the laboratory and in mice, immature white blood cells began to differentiate again, and leukemia development was stopped.

Gleevec is a new type of cancer drug -- the first of its kind developed to fight cancer by turning off an enzyme that causes cells to become cancerous and multiply. In CML, ABL, an enzyme, goes into overdrive because of a chromosomal mix-up that occurs during blood cell development. The genes ABL and BCR become fused and produce a hybrid BCR-ABL enzyme that is always active. The overactive BCR-ABL, in turn, drives the excessive proliferation of white blood cells.

In one study, reactivating C/EBP-alpha in Gleevec-resistant mice cured leukemia in six out of seven animals.

This isn't surprising, Dr. Calabretta says, because C/EBP-alpha isn't involved in the mechanism of action of Gleevec. "Essentially, this is a downstream effect," he explains. "The BCR-ABL protein repressed C/EBP-alpha. In bypassing BCR-ABL, which is the first target, regardless of whether BCR-ABL is normal or mutated (and Gleevec-resistant), turning on C/EBP-alpha will always suppress leukemia. If the function of C/EBP-alpha is introduced in leukemic cells that are resistant to Gleevec because of a mutation, the phenotype is reverted.

"This could be used as a new strategy," he says. "The strategy now against leukemias resistant to BCR-ABL is to develop compounds that may inactivate the mutant -- so called second generation compounds. But another way to do this is to focus on targets downstream."

In the laboratory, the researchers took a cell line in which normal C/EBP-alpha is repressed, and put back another C/EBP-alpha protein. The scientists used an inactive C/EBP-alpha protein that is fused to an estrogen receptor. The protein can only be activated by treating mice with a hormone, in this case tamoxifen, which is used in breast cancer. The receptor responds to tamoxifen. "Now we essentially have an in vivo system in which we have leukemia cells that carry a chimeric protein, C/EBP-alpha-ER," Dr. Calabretta explains. "If you activate CEBP alpha by injection of tamoxifen, this chimeric protein is switched on and suppresses tumorigenesis."

They also were able to halt leukemia in cells resistant to Gleevec. They established a leukemia cell line that expressed a Gleevec-resistant mutation, reactivated the CEBP-alpha, and stopped leukemia development.

Could Gleevec be combined with a product that could also activate C/EBP-alpha, just in case patients develop resistance to the drug?

"The question is, what is more practical to do," he says. "We did a gene transfer experiment -- we put back a gene and activated it. To use C/EBP-alpha as a drug, we would try to deliver it directly." Dr. Calabretta suggests that a better idea might be to identify and deliver a small molecule that can activate the C/EBP-alpha gene.

The discovery could also have applications for other leukemias, he notes, because there are several different mechanisms by which C/EBP-alpha is inactivated. Other scientists have shown that in various types of leukemia, reintroducing C/EBP-alpha can restart differentiation and eliminate leukemia cells.


Story Source:

The above story is based on materials provided by Thomas Jefferson University. Note: Materials may be edited for content and length.


Cite This Page:

Thomas Jefferson University. "New Drug Target Might Sidestep Gleevec Resistance." ScienceDaily. ScienceDaily, 22 September 2006. <www.sciencedaily.com/releases/2006/09/060915202223.htm>.
Thomas Jefferson University. (2006, September 22). New Drug Target Might Sidestep Gleevec Resistance. ScienceDaily. Retrieved October 1, 2014 from www.sciencedaily.com/releases/2006/09/060915202223.htm
Thomas Jefferson University. "New Drug Target Might Sidestep Gleevec Resistance." ScienceDaily. www.sciencedaily.com/releases/2006/09/060915202223.htm (accessed October 1, 2014).

Share This



More Health & Medicine News

Wednesday, October 1, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Some Positive Ebola News: Outbreak 'Contained' In Nigeria

Some Positive Ebola News: Outbreak 'Contained' In Nigeria

Newsy (Sep. 30, 2014) The CDC says a new case of Ebola has not been reported in Nigeria for more than 21 days, leading to hopes the outbreak might be nearing its end. Video provided by Newsy
Powered by NewsLook.com
UN Ebola Mission Head: Immediate Action Is Crucial

UN Ebola Mission Head: Immediate Action Is Crucial

AFP (Sep. 30, 2014) The newly appointed head of the United Nations Mission for Ebola Emergency Response (UNMEER), Anthony Banbury, outlines operations to tackle the virus. Duration: 00:39 Video provided by AFP
Powered by NewsLook.com
CDC Confirms First Case of Ebola in US

CDC Confirms First Case of Ebola in US

AP (Sep. 30, 2014) The CDC has confirmed the first diagnosed case of Ebola in the United States. The patient is being treated at a Dallas hospital after traveling earlier this month from Liberia. (Sept. 30) Video provided by AP
Powered by NewsLook.com
New Breast Cancer Drug Extends Lives In Clinical Trial

New Breast Cancer Drug Extends Lives In Clinical Trial

Newsy (Sep. 30, 2014) In a clinical trial, breast cancer patients lived an average of 15 months longer when they received new drug Perjeta along with Herceptin. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins