Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Writing the Book of Cancer Knowledge

03.04.2012
First volume of the Cancer Cell Line Encyclopedia made public

The goal of cancer treatment is to match the right drug to the right target in the right patient. But before such "personalized" drugs can be developed, more knowledge is needed about specific genomic alterations in cancers and their sensitivity to potential therapeutic agents.

Now an academic-industry collaboration is releasing the first results from a new and freely available resource that marries deeply detailed cancer genome data with predictors of drug response, information that could lead to refinements in cancer clinical trials and future treatments. The Cancer Cell Line Encyclopedia (CCLE), authored by scientists at the Broad Institute, Dana-Farber Cancer Institute, the Genomics Institute of the Novartis Foundation, and the Novartis Institutes for Biomedical Research, is described in the March 29 issue of the journal Nature. In a proof of principle, the researchers also report that genomic predictors of drug sensitivity revealed three novel candidate biomarkers of response.

"We hope that the Cancer Cell Line Encyclopedia will be a preclinical resource that could guide clinical trials," said Levi A. Garraway, a senior associate member of the Broad Institute, an associate professor at Dana-Farber Cancer Institute and Harvard Medical School, and a co-corresponding author of the paper.

"The CCLE is a public resource that we think will catalyze discoveries throughout the cancer research community," said Todd Golub, director of the Broad’s Cancer Program, Charles A. Dana Investigator in Human Cancer Genetics at the Dana-Farber Cancer Institute, and a co-author of the paper. "With this initial effort, we have taken some critical first steps. The challenge now is to greatly expand the number of compounds tested across the panel of cell lines."

The CCLE integrates gene expression, chromosomal copy number, and massively parallel sequencing data from almost 1,000 human cancer cell lines together with pharmacological profiles for 24 anticancer drugs across roughly half of these cell lines. The scale of the project allows greater depth of genetic characterization and pharmacological annotation than previously possible with fewer cell lines. A separate effort by scientists at Massachusetts General Hospital and the Sanger Institute appears in the same issue of Nature.

To accomplish such a feat, the team of scientists relied on the genetics, computational biology, and drug-screening capabilities at the Broad, Dana-Farber, and Novartis. They chose 947 of the nearly 1,200 commercially available cancer cell lines to reflect the genomic diversity of human cancers.

"One of the strengths of the CCLE lies in the number of cell lines it surveys," said Nicolas Stransky, a computational biologist in the Cancer Program at the Broad and a co-first author of the paper. "We can focus on rare cancer subtypes and still have sufficient statistical power for analyses."

Cancer cell lines are malignant cells that have been removed from tumor tissue and cultured in the laboratory. Under controlled conditions, they can grow indefinitely. This near-immortality is an advantage for performing repeated experiments, but it can be a potential pitfall if the cells differ markedly from tumors because they lack typical surroundings. However, with relatively few exceptions, the CCLE cell lines proved to be representative genetic proxies for primary tumor subsets across multiple different cancer types.

Correlating the more than 50,000 genetic and molecular features that emerged from these cell lines created a computational challenge that the scientists met by adapting algorithms to the biological data. They tested this tool against genetic alterations known to predict sensitivity to cancer drugs, and confirmed the value of their systematic approach. Then they applied the predictive modeling methodology to genetic subtypes of cancer known to pose challenges for current treatment modalities.

For example, a variety of cancers have mutations in the NRAS gene, which activates signaling pathways important in tumor growth. Some NRAS-mutant cancers, including a subset of melanomas, may prove vulnerable to drugs that block a protein also involved in signaling, called MEK. The scope of the CCLE enabled the investigators to study approximately 40 cancer cell lines with this mutation to see if they could predict sensitivity to MEK inhibitor drugs, some of which are being studied in clinical trials.

One of the genetic features that rose to the top of their analysis was expression of the aryl hydrocarbon receptor (AHR) gene in cell lines that were highly sensitive to MEK inhibitors. This suggested that high levels of AHR may indicate higher sensitivity to MEK inhibitor drugs. Additional experiments suggested that some of these same cell lines might also depend on AHR activity, and that MEK inhibitors might simultaneously intercept AHR function in some instances.

Armed with this kind of knowledge from the CCLE, researchers may have a much clearer idea of which tumors are most likely to respond to particular drugs before using them in clinical trials, the scientists say. Patients could therefore be selected for such studies based on how likely they are to respond, given the genetic and molecular makeup of their cancers.

"Knowing that kind of information very early might help to improve the success rate of drug development, compared to a genetically 'agnostic' approach that includes any patient with advanced cancer without knowledge of a genetic profile," said Garraway.

The scientists also found new predictors of sensitivity to existing chemotherapy drugs in other cancer cell lines. Elevated levels of SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Another analysis indicates that multiple myeloma may respond to IGF1 receptor inhibitors. Formal clinical studies will be required to learn if these features will hold true in patients.

"We can ask questions not only about emerging targeted therapies, but also about standard chemotherapy drugs," Garraway said. "There may be ways to identify patients who are more likely to respond to conventional chemotherapy versus those who might not. The predicted ‘non-responders’ may be better off trying a different regimen."

There are more volumes to be written in this encyclopedia.

"From a computational biology perspective, it’s a clean, complex data set that allows many more analyses," Stransky said. "We are only scratching the surface of what can be done."

In the CCLE's next phase, analyses based on deeper sequencing, profiles of metabolic activity, and epigenetic modifications – changes in chromatin organization – will also be added.

"This is really the tip of the iceberg," Garraway said. "With these predictive modeling algorithms and with data sets of this size, their study could become an entire discipline in its own right."

Other Broad and Dana-Farber researchers who contributed to this work include Jordi Barretina (now at Novartis), Adam A. Margolin (now at SAGE Biosciences), Lauren Murray, Michael F. Berger, Paula Morais, Adam Korejwa, Judit Jane-Valbuena, Charles Hatton, Emanuele Palescandolo, Supriya Gupta, Scott Mahan, Carrie Sougnez, Robert C. Onofrio, Ted Liefeld, Laura MacConaill, Wendy Winckler, Michael Reich, Jill P. Mesirov, Stacey B. Gabriel, Gad Getz, Kristin Ardlie, and Matthew Meyerson.

The Cancer Cell Line Encyclopedia project was enabled by a grant from the Novartis Institutes for Biomedical Research. Additional funding support was provided by the National Cancer Institute, the Starr Cancer Consortium, and the NIH Director’s New Innovator Award.

The Cancer Cell Line Encyclopedia (CCLE), is available online at http://www.broadinstitute.org/ccle.

-Written by Elizabeth Cooney, Broad Institute

About the Broad Institute of Harvard and MIT
The Eli and Edythe L. Broad Institute of Harvard and MIT was launched in 2004 to empower this generation of creative scientists to transform medicine. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community.

Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to http://www.broadinstitute.org.

About Dana-Farber Cancer Institute
Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It provides adult cancer care with Brigham and Women’s Hospital as Dana-Farber/Brigham and Women’s Cancer Center and it provides pediatric care with Children’s Hospital Boston as Dana-Farber/Children’s Hospital Cancer Center. Dana-Farber is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding. Follow Dana-Farber on Twitter: @danafarber or Facebook: facebook.com/danafarbercancerinstitute

Nicole Davis | Newswise Science News
Further information:
http://www.dana-farber.org

More articles from Health and Medicine:

nachricht 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)

nachricht High speed video recording precisely measures blood cell velocity
15.11.2017 | ITMO University

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

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...

Im Focus: Visual intelligence is not the same as IQ

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...

Im Focus: Novel Nano-CT device creates high-resolution 3D-X-rays of tiny velvet worm legs

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....

Im Focus: Researchers Develop Data Bus for Quantum Computer

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,...

Im Focus: Wrinkles give heat a jolt in pillared graphene

Rice University researchers test 3-D carbon nanostructures' thermal transport abilities

Pillared graphene would transfer heat better if the theoretical material had a few asymmetric junctions that caused wrinkles, according to Rice University...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

Antarctic landscape insights keep ice loss forecasts on the radar

20.11.2017 | Earth Sciences

Filling the gap: High-latitude volcanic eruptions also have global impact

20.11.2017 | Earth Sciences

Water world

20.11.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>