Huge Cancer Knowledge Resource Made PublicFeatured Article
Main Category: Cancer / Oncology
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Article Date: 30 Mar 2012 - 2:00 PDT
Bringing the goal of personalized medicine a step closer, scientists who design anti-cancer treatments and clinical trials now have access to a huge cancer knowledge resource, thanks to a collaboration between industry and academia. A report in the 28 March online issue of Nature describes how the Cancer Cell Line Encyclopedia (CCLE) brings together genome data and predictors of drug response for 947 cancer cell lines.
The ultimate cancer treatment is one that matches the right drug to the right target in the right patient. This is the goal of personalized medicine. But to realize this goal, treatment designers need to know the specific genome alterations in the individual, how sensitive they are to specific drugs, and then tailor the drugs accordingly.
For each cancer cell line, the CCLE compiles information on gene expression, chromosomal copy number, and massively parallel sequencing data. It also contains pharmacological profiles for 24 anticancer drugs across roughly half of the cell lines.
The CCLE is the work of researchers from the Broad Institute, the Dana-Farber Cancer Institute, Harvard Medical School, and the Novartis Institutes for Biomedical Research.
The hope is that the CCLE will provide a rich source of information to help scientists designing the clinical trials to test these drugs.
The Encyclopedia is by no means finished: the researchers say the challenge now is to increase the number of compounds tested across the different cell lines.
The researchers selected 947 of the nearly 1,200 commercially available cancer cell lines to reflect the genomic diversity of human cancers.
Nicolas Stransky, a computational biologist in the Cancer Program at the Broad and a co-first author of the Nature paper, told the press:
"One of the strengths of the CCLE is the number of cell lines it surveys."
"We can focus on rare cancer subtypes and still have sufficient statistical power for analyses," he added.
Cancer cell lines are lab-grown supplies of various types of cancer cell, originally sampled from real tumors. Under controlled lab conditions they can grow indefinitely, ensuring a continuous supply for experiments and trials, without having to keep sampling tissue from people.
While this near "immortality" is an advantage when repeating experiments, it can be a disadvantage if, as a result of being grown in the lab, the cells differ too much from tumor cells that develop in people.
But, apparently, with few exceptions, the CCLE cell lines are well matched genetically to primary tumor subsets across different cancer types.
In what proved to be a considerable computational challenge, the researchers adapted algorithms to the biological data in order to correlate the more than 50,000 genetic molecular features of the cell lines.
They confirmed the value of this approach by comparing their results to genetic alterations already known to predict sensitivity to cancer drugs.
And they used the tool to predict drug sensitivities in genetic subtypes of cancer known to pose challenges for certain treatments.
For instance, some cancers have mutations in the NRAS gene, which triggers signals important for tumor growth. Some cancers with NRAS mutations, such as certain melanomas, may prove vulnerable to drugs that block MEK, a protein that is also involved in signalling.
Using the CCLE "bible", the investigators were able to study about 40 cancer cell lines with this mutation to see if they could predict sensitivity to drugs that inhibit the MEK protein. Some of the drugs are being investigated in trials.
From their analysis they could see that cell lines that were highly sensitive to MEK inhibitors were expressing the aryl hydrocarbon receptor (AHR) gene. This suggests that high levels of AHR may be an indication of higher sensitivity to MEK inhibitors.
On further investigation they found that some of these same cell lines might also depend on AHR, and in some cases, MEK inhibitors could also be intercepting some functions of AHR.
This illustrates how the CCLE can help researchers decide which tumors are most likely to respond to particular drugs before the trial, said the developers.
This would allow participants to be chosen based on how they are likely to respond, because of the genetic and molecular features of their cancers.
The CCLE allows questions not only about emerging targeted therapies, abut also about exisiting chemotherapy drugs.
There could be ways of identifying patients who are more likely to benefit from conventional chemotherapy, as opposed to those who may not, with the latter perhaps being better off with an alternative.
In another example, the scientists describe how using CCLE, they also found new predictors of sensitivity to existing chemotherapy drugs in other cell lines. For instance, higher levels of SLFN11 expression predicted sensitivity to topoisomerase inhibitors.
And another analysis suggests that multiple myeloma may respond to IGF1 receptor inhibitors.
Formal clinical trials would have to be done to confirm if these features will hold true in patients, said the researchers.
The next batch of information to be added to the CCLE will include deeper sequencing, profiles of metabolic activity, and epigenetic modifications.
The research to produce the CCLE was paid for by a grant from the Novartis Institutes for Biomedical Research, with help from National Cancer Institute, the Starr Cancer Consortium, and the NIH Director's New Innovator Award.
Click here to access the CCLE online.
In the same issue of Nature there is a paper on a separate similar catalogue of cancer cell knowledge, compiled by scientists at Massachusetts General Hospital and the Sanger Institute. Click here to see our report on that.
Written by Catharine Paddock PhD
Copyright: Medical News Today
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