Featured Research

from universities, journals, and other organizations

Re-engineered Gleevec Reduces Heart Risks, Study Suggests

Date:
December 5, 2007
Source:
Rice University
Summary:
Using a new bottom-up approach for rational drug design, researchers have reengineered the powerful anticancer drug imatinib -- best known by its brand name Gleevec -- to more specifically target one type of cancer while potentially curbing a rare life-threatening cardiotoxic side effect. The modified drug just as effective against gastrointestinal cancer. The re-design strategy employed in the study is broadly applicable to reducing side effects in other drugs.

Using a new bottom-up approach for rational drug design, researchers at Rice University and the University of Texas M. D. Anderson Cancer Center have reengineered the powerful anticancer drug imatinib -- best known by its brand name Gleevec™ -- to more specifically target one type of cancer while potentially curbing a rare life-threatening cardiotoxic side effect.

The new study reports pre-clinical evidence that the newly re-engineered drug is just as effective as imatinib against gastrointestinal stromal tumor (GIST) and carries significantly less risk of heart failure.

Developed by Novartis Pharmaceuticals, Gleevec is approved by the U.S. Food and Drug Administration for the treatment of chronic myeloid leukemia (CML), Philadelphia-chromosome positive acute lymphoblastic leukemia and GIST. The drug targets two proteins that have been linked with cancer. One of its targets is the C-Kit kinase, a protein that has been tied to gastrointestinal cancer, and another is Bcr-Abl kinase, a key protein controlling CML.

The re-engineered version of imatinib, a new drug dubbed WBZ-4, was designed at Rice, based on a rational strategy developed by Ariel Fernandez, professor of bioengineering.

"Our bottom-up design strategy is also broadly applicable to drugs other than imatinib and enables a rational control and reduction of side effects," said Fernandez.

For example, WBZ-4 was designed to target C-Kit without inhibiting the function of Bcr-Abl, which recent imatinib studies have associated with increased risk for heart failure.

The drug was produced and tested at M.D. Anderson. The research effort is part of the Rice-M. D. Anderson Partnership for Cancer Drug Discovery.

"Imatinib actually affects an entire family of kinases beyond those examined here," said Gabriel Lopez-Berestein, a professor of experimental therapeutics at M. D. Anderson. "This is terrific proof of principle that we can enhance the selectivity of a drug by making a small but significant change in its structure and with precise synthesis and formulation of the new drug. We know exactly how WBZ-4 works. It's a completely novel approach."

In computer models, in vitro assays, and in experimental animals, WBZ-4 was found to be equally effective as regular imatinib at inhibiting C-Kit and halting the growth of GIST cancers. Animal tests also found that the risk of cardiotoxicity was significantly reduced with WBZ-4 compared to imatinib.

"We were successful in our three basic goals in redesigning the drug -- we refocused the primary impact on C-Kit, we reduced the impact on Bcr-Abl, and we reduced cardiotoxicitity," said Fernandez. "Our results corroborate previous findings about the role that Bcr-Abl plays in the cardiotoxicity of imatinib."

Because the re-engineered drug does not target Bcr-Abl, it has no effect against chronic myeloid leukemia or Philadelphia-chromosome positive acute lymphoblastic leukemia, Lopez-Berestein notes. C-Kit, however, is a suspect in other types of cancer.

Previous research showed that inhibition of another tyrosine kinase, JNK, protects against imatinib-induced cardiotoxicity. The research team found that JNK's structure is so similar to C-Kit that the re-engineered drug also inhibits it, Lopez-Berestein says, potentially reinforcing cardiovascular protection.

An accompanying editorial in JCI by George D. Demetri of the Dana-Farber Cancer Institute praises the approach. "The first generation of kinase-inhibitory drugs such as imatinib and sunitinib have already provided patients with life-saving therapeutic options, and with tools such as those described by Fernandez et al., the future certainly looks bright for constructing ever-better agents that can be combined safely and effectively to manage, and eventually cure, many forms of human cancer."

Thomas Force, M.D., Wilson Professor of Medicine at Thomas Jefferson University who published the first findings last year in Nature Medicine implicating ABL inhibition in the risk of heart failure, said the JCI paper is an important step in drug development.

"The reason we had set out to identify the basic mechanisms by which anti-cancer drugs can induce cardiotoxicity was the hope that this knowledge could potentially steer drug development away from targets and pathways that would lead to toxicity, but would leave tumor cell killing intact," Force said. "Fernandez and co-workers, in this really remarkable piece of work, have proven that this is indeed possible. Their findings will hopefully encourage drug makers to pursue a similar approach of 'rational drug re-design' (and drug design) in the development of new anti-cancer agents, thereby retaining anti-cancer activity with limited toxicity."

WBZ-4 is not yet available for human testing. A date for human trials has not been set.

The actual incidence of heart failure among patients taking imatinib is not precisely known but it is low. A retrospective study of leukemia patients taking imatinib at M. D. Anderson showed that 1.7 percent of 1,276 patients had symptoms that could have been caused by heart failure.

"Whether it's a frequent side effect or not, we need to try and understand it," Lopez-Berestein said.

Imatinib has improved the five-year survival rate of chronic myeloid leukemia patients from about half to around 95 percent in less than 10 years.

WBZ-4 was designed and computationally tested by Fernandez, in collaboration with Rice researchers Jianpeng Ma, Alejandro Crespo, Jianpeng Chen, Sarah Wulf and M. D. Anderson's Angela Sanguino. It is identical to imatinib, except for the addition of four atoms -- a carbon and three hydrogens -- at a key point. This addition forms a molecular bandage, or wrapper, that is designed to keep water molecules away from a key reaction site on C-KIT not present in Bcr-Abl. By positioning the wrapper in precisely the right spot, the designers were able to ensure that WBZ-4 would not inhibit the effect of Bcr-Abl. This "wrapping design strategy" is the key to controlling drug specificity.

"KIT, Bcr-Abl and virtually all other proteins have subtle structural defects that leave some parts of the structure poorly shielded from water attack," Fernandez said. "These bonds are known as 'dehydrons,' and our study clearly shows the critical role that they play in rational drug design."

On paper, adding just four atoms to imatinib would appear to be simple. In reality, this tiny change required an entirely new chemical synthesis that was both complex and challenging. The synthesis was developed by Prof. William Bornmann, the director of M.D. Anderson's Center for Targeted Therapy's Translational Chemistry Service, and his colleague Zhenghong Peng.

Following the drug's synthesis, several teams of researchers embarked on a comprehensive program to test and evaluate the drug. WBZ-4 was incorporated into liposomal nanoparticles -- tiny balls of fat -- to facilitate drug formulation and drug delivery to the tumor cells. Testing was overseen by M.D. Anderson's Lopez-Berestein and Anil Sood, professor of cancer biology, who developed a mouse model of GIST and CML to test the drug. Loyola University Medical Center's Allen Samarel conducted in vitro testing for cardiotoxicity.

This research was published in the Dec. 3 issue of the Journal of Clinical Investigation.

Additional co-authors are: Eylem Ozturk, Aleksander Shavrin, Jonathan Trent, Yvonne Lin, Hee-Dong Han, Lingegowda Mangala, James Bankston, and Juri Gelovani, all of M.D. Anderson; and Chaoping Qin of Baylor College of Medicine.

The research was funded by the National Institutes of Health, the Gulf Coast Center for Computational Cancer Research, the Welch Foundation, the National Cancer Institute and the Ovarian Cancer Research Fund.


Story Source:

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


Cite This Page:

Rice University. "Re-engineered Gleevec Reduces Heart Risks, Study Suggests." ScienceDaily. ScienceDaily, 5 December 2007. <www.sciencedaily.com/releases/2007/12/071203190607.htm>.
Rice University. (2007, December 5). Re-engineered Gleevec Reduces Heart Risks, Study Suggests. ScienceDaily. Retrieved July 30, 2014 from www.sciencedaily.com/releases/2007/12/071203190607.htm
Rice University. "Re-engineered Gleevec Reduces Heart Risks, Study Suggests." ScienceDaily. www.sciencedaily.com/releases/2007/12/071203190607.htm (accessed July 30, 2014).

Share This




More Health & Medicine News

Wednesday, July 30, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Health Insurers' Profits Slide

Health Insurers' Profits Slide

Reuters - Business Video Online (July 30, 2014) Obamacare-related costs were said to be behind the profit plunge at Wellpoint and Humana, but Wellpoint sees the new exchanges boosting its earnings for the full year. Fred Katayama reports. Video provided by Reuters
Powered by NewsLook.com
Concern Grows Over Worsening Ebola Crisis

Concern Grows Over Worsening Ebola Crisis

AFP (July 30, 2014) Pan-African airline ASKY has suspended all flights to and from the capitals of Liberia and Sierra Leone amid the worsening Ebola health crisis, which has so far caused 672 deaths in Guinea, Liberia and Sierra Leone. Duration: 00:43 Video provided by AFP
Powered by NewsLook.com
At Least 20 Chikungunya Cases in New Jersey

At Least 20 Chikungunya Cases in New Jersey

AP (July 30, 2014) At least 20 New Jersey residents have tested positive for chikungunya, a mosquito-borne virus that has spread through the Caribbean. (July 30) Video provided by AP
Powered by NewsLook.com
Generics Eat Into Pfizer's Sales

Generics Eat Into Pfizer's Sales

Reuters - Business Video Online (July 29, 2014) Pfizer, the world's largest drug maker, cut full-year revenue forecasts because generics could cut into sales of its anti-arthritis drug, Celebrex. Fred Katayama reports. Video provided by Reuters
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:
from the past week

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