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!
Researchers uncover protein-based “cancer signature”
05.12.2016 | Universität Basel
The Nagoya Protocol Creates Disadvantages for Many Countries when Applied to Microorganisms
05.12.2016 | Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
05.12.2016 | Power and Electrical Engineering
05.12.2016 | Materials Sciences
05.12.2016 | Power and Electrical Engineering