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!
The birth of a new protein
20.10.2017 | University of Arizona
Building New Moss Factories
20.10.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau
University of Maryland researchers contribute to historic detection of gravitational waves and light created by event
On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...
Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.
Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....
Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).
When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...
Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.
How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...
Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.
It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...
17.10.2017 | Event News
10.10.2017 | Event News
10.10.2017 | Event News
20.10.2017 | Information Technology
20.10.2017 | Materials Sciences
20.10.2017 | Interdisciplinary Research