The brain tumor afflicting Sen. Edward Kennedy – a glioblastoma – is the most aggressive and wily form of brain cancer. It has foiled researchers' decades-long efforts to thwart its explosive growth in the brain.
The lethal tumor – the most common brain tumor in humans -- nimbly alters its genes like a quick-change artist to elude treatments to destroy it.
But scientists from Northwestern University Feinberg School of Medicine have discovered the formidable tumor's soft underbelly. They have identified a network of 31 mutated genes that stealthily work together to create the perfect molecular landscape to allow the tumor to flourish and mushroom to the size of an apple in just a few months.
Northwestern researchers have also identified a new gene, Annexin A7, a vital guard whose job is to halt tumor growth and whose level in the tumor predicts how long a glioblastoma patient will survive. The genetic landscape of glioblastomas eliminates Annexin A7 by wiping out its home base, chromosome 10.
The discoveries help researchers understand the tumor's vulnerabilities and offer new targets for therapies to treat the disease.
"These 31 genes are the kingpins in what you could call an organized crime network of genes that enable the tumor to grow with breathtaking speed," said Markus Bredel, M.D., director of the Northwestern Brain Tumor Institute research program, assistant professor of neurological surgery at the Feinberg School and the principal investigator of the two studies reporting these new findings. "These 31 genes are highly connected to and affect hundreds of other genes involved in this process."
The studies will be published in the July 15 issue of Journal of the American Medical Association.
It was no small task for Bredel to identify the kingpins of the network. Glioblastomas are among the most biologically complex cancers, involving changes in thousands of genes. Leukemia, by contrast, involves changes in just a few genes.
Bredel said the way to identify the key players was to determine which genes had the most connections to other genes in the network. "We don't care about the gangster on the street. We wanted to find the big bosses," Bredel said. "If you knock them out, then you have a big effect on all the other genes in the network."
To accomplish that, Bredel and colleagues looked at the molecular levels and genetic profiles of more than 500 brain tumors of patients from around the country as well as the clinical profiles of the patients. Bredel's first study reports on the 31 key mutated genes he discovered that comprise the tumor's primary network. These genes represent a recurrent pattern of the most important mutations in the tumor.
"If many of those genes were mutated, the more aggressive the tumor and the less time the patient would survive," Bredel said. These are called hub genes because they are at the hub of all the mutated gene interaction.
In the second study, Bredel reports on the interaction of two of the 31 genes that are most frequently and concurrently affected by genetic alterations. One of those genes is EGFR (epidermal growth factor receptor), a well-known player in many cancers and known as an oncogene. EGFR has physiological importance in normal development. In nearly half of the glioblastoma patients, EGFR is mutated and abnormally activated, as if its dial is cranked permanently to "high."
Bredel discovered that the other gene, Annexin A7, is a vital guard whose job is to halt tumor growth by regulating the EGFR gene. Bredel found Annexin A7 was lost or diminished in many of the patients' malignant brain tumors. The reason was its home base -- chromosome 10 -- had been wiped out in about 75% of the tumors.
The study showed the presence and quantity of Annexin A7 in the malignant brain tumor accurately predicts how long a glioblastoma patient will survive. The more Annexin A7, the more restrictions on the tumor growth and the longer the survival. Bredel said the identification of Annexin A7 as a major regulator of EGFR provides a biological reason for the frequent parallel loss of chromosome 10 and gain of the EGFR gene in glioblastomas.
In the laboratory, Bredel tested the relationship between EGFR and Annexin A7 to try to understand exactly how they affected the tumor. Working with brain tumor cells, Bredel increased the level of EGFR and, in parallel, knocked out Annexin A7. The tumor cells grew much faster compared to tumor cells in which only one gene was modified.
"It's like a 'buy two, get one free' sale," Bredel said. "The tumor says, 'I'm making a good deal. I'm going to buy those two mutations because it's going to be very rewarding for me'."
With one mutation that increased EFGR and the other that eliminated chromosome 10 and Annexin A7, the tumor was free to proliferate unchecked.
"Understanding the key role of Annexin A7 in malignant brain tumors offers the opportunity for a new therapeutic target," Bredel said. "The challenge is now that we've established that this gene is important, how can we modulate it through molecular cancer therapy?"
"We want to extend the survival of the patients, transform this hyper-acute disease into a more chronic tumor disease," Bredel said. "Maybe someday, a glioblastoma patient will be able to live for 10 or 20 years after a diagnosis."
Marla Paul | EurekAlert!
A novel synthetic antibody enables conditional “protein knockdown” in vertebrates
20.08.2018 | Technische Universität Dresden
Climate Impact Research in Hannover: Small Plants against Large Waves
17.08.2018 | Leibniz Universität Hannover
There are currently great hopes for solid-state batteries. They contain no liquid parts that could leak or catch fire. For this reason, they do not require cooling and are considered to be much safer, more reliable, and longer lasting than traditional lithium-ion batteries. Jülich scientists have now introduced a new concept that allows currents up to ten times greater during charging and discharging than previously described in the literature. The improvement was achieved by a “clever” choice of materials with a focus on consistently good compatibility. All components were made from phosphate compounds, which are well matched both chemically and mechanically.
The low current is considered one of the biggest hurdles in the development of solid-state batteries. It is the reason why the batteries take a relatively long...
New design tool automatically creates nanostructure 3D-print templates for user-given colors
Scientists present work at prestigious SIGGRAPH conference
Most of the objects we see are colored by pigments, but using pigments has disadvantages: such colors can fade, industrial pigments are often toxic, and...
Scientists at the University of California, Los Angeles present new research on a curious cosmic phenomenon known as "whistlers" -- very low frequency packets...
Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.
When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...
Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.
Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....
17.08.2018 | Event News
08.08.2018 | Event News
27.07.2018 | Event News
20.08.2018 | Information Technology
20.08.2018 | Life Sciences
20.08.2018 | Information Technology