Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New research strategy for understanding drug resistance in leukemia

08.09.2009
UCSF researchers have developed a new approach to identify specific genes that influence how cancer cells respond to drugs and how they become resistant.

This strategy, which involves producing diverse genetic mutations that result in leukemia and associating specific mutations with treatment outcomes, will enable researchers to better understand how drug resistance occurs in leukemia and other cancers, and has important long-term implications for the development of more effective therapies.

Findings are reported in the Advance Online Publication of the journal “Nature” and are available at http://www.nature.com/nature/journal/vaop/ncurrent/index.html.

“In trying to understand why certain cancers respond to drugs while certain other cancers fail to respond, we found that a single gene can be the culprit for drug resistance,” said Kevin Shannon, MD, senior author of the paper and a pediatric cancer specialist at UCSF Children’s Hospital. “The subtlety of what makes a cancer cell become resistant to a drug is truly remarkable.”

“When treating patients for cancer, clinical specialists usually only have one or two chances to choose the right drug before it is too late. This makes it incredibly important to understand drug resistance so that we can prioritize therapeutic options,” said Jennifer Lauchle, MD, the study’s lead author and a pediatric blood and cancer specialist at UCSF Children’s Hospital.

In the initial stages of the study, the researchers used a strain of mice that developed acute myelogenous leukemia, or AML, to assess the effectiveness of an experimental cancer drug called a MEK inhibitor. AML is an aggressive cancer that affects both children and adults and causes abnormal white blood cells to grow rapidly and accumulate in the bone marrow, thereby interfering with the production of normal blood cells.

The researchers created the mouse model of AML through two key steps. First they utilized a strain of mice that had a single gene mutation closely resembling the mutation found in leukemia and some other cancers. Then they introduced an infectious particle called a retrovirus, which produces additional mutations that work together and result in AML. The retrovirus also “tags” these new genetic mutations, which allows researchers to identify them later on. These steps resulted in a model of AML that, like human AML and other advanced cancers, has several genetic mutations that interact with one another.

To assess the effectiveness of the MEK inhibitor, the researchers compared a group of mice with AML that was treated with the drug to a group that was left untreated and found that the drug increased survival time threefold. However, all of the leukemia cells that initially responded to the drug later relapsed, which is similar to what happens in many human patients.

“This shows that even if you make what seems to be a really good drug, resistance is a major problem that must be overcome,” said Shannon, who is also a leader of the hematopoietic malignancies research program at UCSF’s Helen Diller Family Comprehensive Cancer Center.

In the next phase of the study, the research team set out to uncover the genes that triggered drug resistance by comparing cells from the original drug responsive AML to those of the relapsed AML. Because AML in the mouse model had been created with a retrovirus, the new mutations that caused the leukemia to relapse could be pinpointed through forward genetic analyses. These analyses identified two new single gene mutations that rendered the MEK inhibitor ineffective and brought about the relapsed AML.

According to the researchers, this same method can be used to study other types of cancer in order to identify additional genes responsible for drug resistance. “The hope is that this new strategy will enable us to identify more effective therapies and to find ways to anticipate and overcome drug resistance,” Shannon added.

Additional co-authors from UCSF include Doris Kim, Doan Le, MD, Michael Crone, Kimberly Krisman, Kegan Warner, Jeannette Bonifas, Qing Li, MD, Kristen Coakley, Ernesto Diaz-Flores, PhD, Matthew Gorman, MD, Mary Tran, Scott Kogan, MD, and Jeroen Roose, PhD. Co-authors from other institutions are Keiko Akagi, PhD, and Linda Wolff, PhD, of the National Cancer Institute; Sally Przybranowski, MS, and Judith Sebolt-Leopold, PhD, of Pfizer Global Research and Development; Neal Copeland, PhD, and Nancy Jenkins, PhD, of the Institute of Molecular and Cell Biology; and Luis Parada, PhD, of the University of Texas Southwestern.

The research was supported by grants from the National Institutes of Health, the Leukemia and Lymphoma Society, the US Army Neurofibromatosis Research Program, the Ronald McDonald House Charities of Southern California/Couples Against Leukemia, the Jeffrey and Karen Peterson Family Foundation, and the Frank A. Campini Foundation.

One of the nation’s top children’s hospitals, UCSF Children’s Hospital creates an environment where children and their families find compassionate care at the healing edge of scientific discovery, with more than 150 experts in 50 medical specialties serving patients throughout Northern California and beyond. The hospital admits about 5,000 children each year, including 2,000 babies born in the hospital.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

Kate Schoen | EurekAlert!
Further information:
http://www.ucsf.edu

Further reports about: AML Cancer MEK UCSF blood cell gene mutation genetic mutation leukemia mouse model white blood cell

More articles from Life Sciences:

nachricht Link Discovered between Immune System, Brain Structure and Memory
26.04.2017 | Universität Basel

nachricht Researchers develop eco-friendly, 4-in-1 catalyst
25.04.2017 | Brown University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

Millions through license revenues

27.04.2017 | Health and Medicine

The TU Ilmenau develops tomorrow’s chip technology today

27.04.2017 | Information Technology

Scientist invents way to trigger artificial photosynthesis to clean air

26.04.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>