Glioblastoma is one of the deadliest malignancies, typically killing patients within 12 to 18 months. These brain cancers consist of two kinds of cells, a larger, heterogeneous population of tumor cells and a smaller sub-population of stem cells, which are treatment-resistant.
The screening system was specifically designed to find drugs that can target that sub-population and prevent it from re-seeding the brain cancer, said study senior author Dr. Harley Kornblum, a Jonsson Cancer Center scientist and a professor of psychiatry and biobehavioral sciences.
“We’re pleased that we can present a different way to approach the discovery of potential new cancer drugs,” said Kornblum, who also is a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “And by finding these drugs, we may be able to reveal things about the biology of these cancer stem cells.”
The study appears in the Oct. 10 issue of Molecular Cancer Therapeutics, a peer-reviewed journal of the American Association of Cancer Research.
After testing more than 31,000 compounds from seven chemical libraries in an initial screen, the team came up with 694 that showed some activity against the brain cancer stem cells. After further narrowing the field down to 168 compounds, they decided to focus on four in future studies because they most successfully inhibited the brain cancer stem cells, Kornblum said.
What Kornblum and his team did in their approach was sort of a reverse of the usual screening processes. Typically, researchers doing high-throughput screening are seeking a drug to hit a specific target they know is on a cancer cell, perhaps a protein that is causing it to grow or a gene that keeps it from dying. In this case, Kornblum said, the team was basically shooting in the dark because the biology of these brain cancer stem cells is largely unknown.
“When brain cancer stem cells were first discovered, we all realized rapidly that we would need to find drugs that attack these cells specifically, because they’re resistant to our conventional therapies,” Kornblum said. “We needed a way to kill these stem cells.”
UCLA’s high-throughput screening technology is capable of screening as many as 100,000 compounds in a single day. Researchers generally develop cancer cells lines and then create an assay, a procedure in molecular biology to test or measure the activity of a drug or biochemical compound in an organic sample, in this case the cancer cells.
The cells are loaded into plates with 384 wells each and the drugs are added. The plates are about the size of the palm of an adult hand. The computerized, robotic screening system executes the process from start to finish, adding the compounds sitting in the tiny wells in the plates to the cancer cells, located in corresponding assay plates.
In this study, Kornblum and his team had a few clues to help them in narrowing down potential candidates that kill brain cancer stem cells. One method they used was based on a prior discovery by Jonsson Cancer Center researchers. The researchers had identified genes that correlate with how aggressive a brain tumor is, so Kornblum decided to try to find potential drug candidates that might reduce the expression of these genes. Another approach was to figure out which of the molecules killed brain cancer stem cells with a greater potency than they attacked other cells within glioblastoma.
To grow his cell lines, Kornblum used human tissue taken from UCLA patients diagnosed with glioblastoma. He knew that a certain method of culturing brain cancer cells resulted in a large number of brain cancer stem cells in the population. These cells were then screened with a molecular library of 31,624 compounds available through the cancer center’s Molecular Screening Shared Resource. These compounds encompass a wide range of structures and therefore have the possibility of influencing virtually all cellular functions.
“We decided on this type of approach because, although we have learned a great deal about brain cancer stem cells in the past several years, we still have not discovered enough of their biology to be sure that any single target will be the right one to hit,” Kornblum said.
Going forward, Kornblum and his team will further study the four identified “lead” compounds to see if they help reveal the biology of the brain cancer stem cells and potentially result in a new and more effective therapy for these deadly brain cancers.
“One of our goals was to determine whether some compounds selectively act on glioblastoma stem cells compared to the less tumorigenic cells from the same tumor,” the study states. “This selectivity may allow for the delineation of pathways and processes that are highly important to these cells. By making sure that a drug candidate has the potential to attack these stem cells, one might ensure the highest chance of therapeutic success.”
Funding for the study was provided by the Jonsson Comprehensive Cancer Center, the National Cancer Institute and the National Institute of Neurological Disorders and Stroke.
UCLA's Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2011, the Jonsson Cancer Center was named among the top 10 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 11 of the last 12 years. For more information on the Jonsson Cancer Center, visit our website at http://www.cancer.ucla.edu.
Kim Irwin | Newswise Science News
Individual Receptors Caught at Work
19.10.2017 | Julius-Maximilians-Universität Würzburg
Rapid environmental change makes species more vulnerable to extinction
19.10.2017 | Universität Zürich
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
19.10.2017 | Materials Sciences
19.10.2017 | Materials Sciences
19.10.2017 | Physics and Astronomy