After years of rigorous research, a team of scientists has identified the genetic engine that drives a rare form of liver cancer. The findings offer prime targets for drugs to treat the usually lethal disease, fibrolamellar hepatocellular carcinoma (FL-HCC), which mainly strikes adolescents and young adults.
Sanford Simon, who conducted the research as head of The Rockefeller University's Laboratory of Cellular Biophysics, describes the culprit as a "chimeric gene," a mutation created when two genes fuse together. These genes normally sit far apart from each other, separated by some 400,000 base pairs, the building blocks of DNA that combine to form genes.
The chimeric gene, which Simon's lab first characterized three years ago, has been found in each of the hundreds of FL-HCC patients tested for the mutation.
A disease mechanism revealed
Having confirmed the chimeric gene as a hallmark of the disease, Simon set out to explore if and how it may cause these malignant tumors. He worked with Scott Lowe, a cancer geneticist at the Memorial Sloan Kettering Cancer Center, to develop a mouse model of FL-HCC.
In work published this week in the Proceedings of the National Academy of Sciences, the scientists used CRISPR gene editing, a highly precise tool for manipulating DNA, to generate mice that carry the 400,000 base-pair deletion and produce the chimeric gene.
Edward Kastenhuber, a graduate student in Lowe's lab, found that these mice develop liver tumors that mimic the biology of the tumors found in humans with FL-HCC, suggesting that the deletion is in itself sufficient to cause the cancer--other alterations are not necessary for tumors to grow.
However, this experiment left open the question of precisely how the deletion spurs cancer: by eliminating genes that normally would suppress the growth of tumors, or by introducing the chimeric gene. Another experiment, in which mice with the fused gene but no deletion in the genome developed tumors, proved that it's the mutation, not the missing DNA as such, that causes the disease.
With the chimeric gene firmly established as the driver of the disease, and its cellular mechanisms defined, Simon and his team--including Gadi Lalazar, of Rockefeller's Clinical Scholars Program, and graduate student David Requena--are now working to identify potential targets for drugs to treat the disease.
New concepts for therapy
Among these drug targets is a protein produced from the fused gene that belongs to a family of enzymes called kinases. These enzymes are often mutated in cancers. "In fact," Simon explains, "some of the most successful cancer therapies available, including Gleevec, act by targeting specific kinases."
The researchers showed that disruption of the fused gene's kinase activity impaired the formation of tumors in mice--a finding that has strengthened their confidence that agents aimed at targeting this activity or its consequences might be effective against FL-HCC.
The team is also studying the effects of targeting a number of cellular signaling systems that have previously been implicated in other cancers, and that speed tumor growth when they become overactive in FL-HCC patients. And they will be using their new mouse model as a system to test the effectiveness of new therapies prior to initiating clinical trials in patients.
Simon first became interested in FL-HCC nine years ago, when his 12-year-old daughter Elana was diagnosed with the disease. (Now 21, Elana is a senior at Harvard, and a lead author on earlier reports characterizing the genomics of the disease.) He continues to embrace the challenge the cancer presents and attributes the latest breakthroughs to an "incredible perfect storm" of advances in all of the sciences, thanks to decades of public investment in basic research.
"Here's a cancer where, five years ago, we didn't know if it was one disease or many diseases lumped together," Simon adds. "We didn't know if it was inherited or if it was due to a sporadic mutation. And now we know exactly what the driver is and how it works, and we can start designing therapeutics."
Katherine Fenz | EurekAlert!
Penn study identifies new malaria parasites in wild bonobos
21.11.2017 | University of Pennsylvania School of Medicine
NIST scientists discover how to switch liver cancer cell growth from 2-D to 3-D structures
17.11.2017 | National Institute of Standards and Technology (NIST)
The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.
Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.
During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....
The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.
Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
22.11.2017 | Medical Engineering
22.11.2017 | Materials Sciences
22.11.2017 | Health and Medicine